Trpv1 antagonists including dihydroxy substituent and uses thereof

ABSTRACT

The invention relates to compounds of formula IA 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formula IA or a pharmaceutically acceptable derivative thereof.

This application claims the benefit of U.S. provisional application No.60/926,661, filed Apr. 27, 2007, U.S. provisional application No.60/930,036, filed May 11, 2007, U.S. provisional application No.60/937,003, filed Jun. 21, 2007, and U.S. provisional application No.60/962,409, filed Jul. 27, 2007, the disclosure of each of which isincorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The invention relates to compounds of formula I, and pharmaceuticallyacceptable derivatives thereof, compositions comprising an effectiveamount of a compound of formula I and methods for treating or preventinga condition such as pain, UI, an ulcer, IBD, and IBS, comprisingadministering to an animal in need thereof an effective amount of acompound of formula I.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or central nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at vanilloid receptors (V. Di Marzoet al., Current Opinion in Neurobiology 12:372-379 (2002)) to painprocessing.

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.,gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDAantagonists (e.g., ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.,fluoxetine, sertraline and amitriptyline).

UI is uncontrollable urination, generally caused bybladder-detrusor-muscle instability. UI affects people of all ages andlevels of physical health, both in health care settings and in thecommunity at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle overactivity.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered.

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more women than men. In IBS, stimulisuch as stress, diet, drugs, hormones, or irritants can cause thegastrointestinal tract to contract abnormally. During an episode of IBS,contractions of the gastrointestinal tract become stronger and morefrequent, resulting in the rapid transit of food and feces through thesmall intestine, often leading to diarrhea. Cramps result from thestrong contractions of the large intestine and increased sensitivity ofpain receptors in the large intestine.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow ed., 1997).

International publication no. WO 98/31677 describes a class of aromaticamines derived from cyclic amines that are useful as antidepressantdrugs.

International publication no. WO 01/027107 describes a class ofheterocyclic compounds that are sodium/proton exchange inhibitors.

International publication no. WO 99/37304 describes substitutedoxoazaheterocycly compounds useful for inhibiting factor Xa.

U.S. Pat. No. 6,248,756 to Anthony et al. and international publicationno. WO 97/38665 describe a class of piperidine-containing compounds thatinhibit farnesyl-protein transferase (Ftase).

International publication no. WO 98/31669 describes a class of aromaticamines derived from cyclic amines useful as antidepressant drugs.

International publication no. WO 97/28140 describes a class ofpiperidines derived from1-(piperazin-1-yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that areuseful as 5-HT_(1Db) receptor antagonists.

International publication no. WO 97/38665 describes a class ofpiperidine containing compounds that are useful as inhibitors offarnesyl-protein transferase.

U.S. Pat. No. 4,797,419 to Moos et al. describes a class of ureacompounds for stimulating the release of acetylcholine and useful fortreating symptoms of senile cognitive decline.

U.S. Pat. No. 5,891,889 describes a class of substituted piperidinecompounds that are useful as inhibitors of farnesyl-protein transferase,and the farnesylation of the oncogene protein Ras.

U.S. Pat. No. 6,150,129 to Cook et al describes a class of dinitrogenheterocycles useful as antibiotics.

U.S. Pat. No. 5,529,998 to Habich et al describes a class ofbenzooxazolyl- and benzothiazolyloxazolidones useful as antibacterials.

International publication no. WO 01/57008 describes a class of2-benzothiazolyl urea derivatives useful as inhibitors ofserine/threonine and tyrosine kinases.

International publication no. WO 02/08221 describes aryl piperazinecompounds useful for treating chronic and acute pain conditions, itch,and urinary incontinence.

International publication no. WO 00/59510 describes aminopyrimidinesuseful as sorbitol dehydrogenase inhibitors.

Japanese patent application no. 11-199573 to Kiyoshi et al. describesbenzothiazole derivatives that are neuronal 5HT3 receptor agonists inthe intestinal canal nervous system and useful for treating digestivedisorders and pancreatic insufficiency.

German patent application no 199 34 799 to Rainer et al. describes achiral-smectic liquid crystal mixture containing compounds with 2 linked(hetero)aromatic rings or compounds with 3 linked (hetero)aromaticrings.

M. Chu-Moyer et al., J. Med. Chem. 45:511-528 (2002) describesheterocycle-substituted piperazino-pyrimidines useful as sorbitoldehydrogenase inhibitors.

B. G. Khadse et al., Bull. Haff. Instt. 1(3):27-32 (1975) describes2-(N⁴-substituted-N¹-piperazinyl)pyrido(3,2-d)thiazoles and5-nitro-2-(N⁴-substituted-N¹-piperazinyl)benzthiazoles useful asanthelmintic agents.

U.S. Patent Application Publication No. US 2004/0186111 A1 andInternational publication no. WO 2004/058754 A1 describe a class ofcompounds that are useful for treating pain.

U.S. Patent Application Publication No. US 2006/0199824-A1 andInternational publication no. WO 2005/009987 A1 describe a class ofcompounds that are useful for treating pain.

U.S. Patent Application Publication No. US 2006/0128717 A1 andInternational publication no. WO 2005/009988 A1 describe a class ofcompounds that are useful for treating pain.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, UI, an ulcer, IBD, and IBS. Citation of anyreference in Section 2 of this application is not to be construed as anadmission that such reference is prior art to the present application.

3. SUMMARY OF THE INVENTION

The invention encompasses compounds of formula I:

or a pharmaceutically acceptable derivative thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C, N, or O;

wherein no more than one of Y₁, Y₂, or Y₃ can be O, and for each Y₁, Y₂,and Y₃ that is N, the N is bonded to one R₂₁ group, and for each Y₁, Y₂,and Y₃ that is C, the C is bonded to two R₂₀ groups, provided that thereare no more than a total of two (C₁-C₆)alkyl groups substituted on allof Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, —NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, —(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CH₂—OR₇,-phenyl, or -halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —N(R₂₀)₂;

J is —OR₂₀, —SR₂₀, —N(R₂₀)₂, or —CN;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, then Z₂ is not -halo;

each R₃ is independently:

-   -   (a) —H, —CH₂OR₇, or —(C₁-C₆)alkyl; or    -   (b) two R₃ groups together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups, and which bridge optionally contains —HC═CH—        within the (C₂-C₆)bridge; or    -   (c) two R₃ groups together form a —CH₂—N(R_(a))—CH₂— bridge, a

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b)-phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups;

each R_(c) is independently —H or —(C₁-C₄)alkyl;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ is independently:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, or -phenyl, each of        which is unsubstituted or substituted with 1 or 2-OH groups; or    -   (b) —H, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo),        —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —SC(halo)₃, —SCH(halo)₂,        —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,        —N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇,        —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy(C₃-C₈)cycloalkyl, —CN, —OH,-halo, —OC(halo)₃, —N₃, —NO₂, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,—O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇,—N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂,—SO₂C(halo)₃, —SO₂(3- to 7-membered)heterocycle, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl;

each R₂₁ is independently —H, —(C₁-C₆)alkyl,

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

Compounds of formula I are potent at TRPV1 receptors, and are highlysoluble in aqueous solutions at either pH 6.8 or pH 1.2.

A compound of formula I, or a pharmaceutically acceptable derivativethereof, is useful for treating or preventing pain, UI, an ulcer, IBD,or IBS (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a compound of formula I, or a pharmaceutically acceptablederivative thereof, and a pharmaceutically acceptable carrier orexcipient. The compositions are useful for treating or preventing aCondition in an animal.

The invention further relates to methods for treating a Conditioncomprising administering to an animal in need thereof an effectiveamount of a compound of formula I, or a pharmaceutically acceptablederivative thereof.

The invention further relates to use of a compound of formula I in themanufacture of a medicament for treating and/or preventing a Condition.

The invention further relates to methods for preventing a Conditioncomprising administering to an animal in need thereof an effectiveamount of a compound of formula I, or a pharmaceutically acceptablederivative thereof.

The invention still further relates to methods for inhibiting TransientReceptor Potential Vanilloid 1 (“TRPV1,” formerly known as VanilloidReceptor 1 or VR1) function in a cell, comprising contacting a cellcapable of expressing TRPV1 with an effective amount of a compound offormula I, or a pharmaceutically acceptable derivative thereof.

The invention still further relates to a method for preparing acomposition comprising the step of admixing a compound of formula I, ora pharmaceutically acceptable derivative thereof, and a pharmaceuticallyacceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a compound of formula I, or apharmaceutically acceptable derivative thereof.

In one embodiment, preferred compounds of formula I are compounds offormula IA:

or a pharmaceutically acceptable derivative thereof, where the dashedline, W, X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above forcompounds of formula I, wherein Q is

and wherein Z₁, Z₂, Z₃, Z₄, and J are as defined above for compounds offormula I.

Preferred compounds of formula I are compounds of formula II:

or a pharmaceutically acceptable derivative thereof, where the dashedline, W, X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above forcompounds of formula I,wherein Q is

Z₁ is —OH, —SH, —N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H, —CH₃, or —CH₂—OR₇;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

Compounds of formula II are highly soluble in aqueous solutions ateither pH 6.8 or pH1.2, are very potent at the TRPV1 receptor, have goodbioavailability, and have a good therapeutic index.

Preferred compounds of formula II are compounds of formula III:

or a pharmaceutically acceptable derivative thereof, where the dashedline, W, X, Ar₁, Ar₂, R₃, R₄, and m are as defined above for compoundsof formula I,

wherein Ar₁ is:

R₁ is —Cl, —F, or —CF₃;

wherein Ar₂ is:

R₁₄ is —H, —Cl, —F, —Br, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is —H,—CF₃, —OCF₃, —Cl, or —F;

R_(14′) is —H, —Cl, —F, —Br, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is —H,—CF₃, —OCF₃, —Cl, or —F; and

each R₈ and R₉ is independently —H, —Cl, —Br, —F, —CH₃, —OCH₃, —OCH₂CH₃,—CF₃, —OCF₃, iso-propyl, or tert-butyl.

Compounds of formula III are highly soluble in aqueous solutions ateither pH 6.8 or pH 1.2, are exceptionally potent at TRPV1 receptors,have excellent bioavailability, have a high therapeutic index, and arebelieved to be highly efficacious in animals for the treatment of pain.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. 96-well plate with different agonist solutions (Agonist Plate).Seven different sulfuric acid solutions, or agonist solutions, withdifferent sulfuric acid (H₂SO₄) concentrations (of from 15.0 mM to 18 mMas indicated) were used for the pH assay as indicated. For the wells inrow A, measuring buffer alone was used. The final concentration ofsulfuric acid in the wells for each row, after a 1:4 dilution of theagonist solution, is also indicated in each row in parenthesis.

FIG. 2. pH dependent Ca²⁺ responses in TRPV1/CHO cells. Ca²⁺ influx intoTRPV1/CHO cells as measured by Fura-2 AM fluorescence is indicated bythe graph within each rectangular field. The graph presents thefluorescence intensity over time starting from the addition of agonistsolution. Each rectangular field presents one experiment performed inone well of a 96-well plate. Each row presents six experiments performedat the same final sulfuric acid concentration; the final sulfuric acidconcentration is indicated at the left. Actual pH values were measuredafter the experiment and are indicated above the graph. No antagonistswere added to the cell culture. Final sulfuric acid concentrations of3.2 and 3.3 mM produced an appropriate Ca²⁺ response and were selectedfor subsequent assays. These final sulfuric acid concentrations can beobtained by 1:4 dilutions of agonist solution with sulfuric acidconcentrations of 16.0 mM or 16.5 mM, respectively (see FIG. 1).

FIG. 3. (A) A 96-well plate with two different sulfuric acidconcentrations. Wells in columns 1 to 6 had one final sulfuric acidconcentration; wells in columns 7 to 12 had a different final sulfuricacid concentration. The final sulfuric acid concentration was reached by1:4 dilution of two different agonist solutions with sulfuric acidconcentrations of X mM and (X+0.5) mM, respectively. In the experimentdescribed in Section 2 of Protocol 2, X was determined to be 16 mM. (B)A 96-well plate with different test compound, or antagonist,concentrations indicated in nM. Only one kind of test compound wasapplied per 96-well plate. Since two different sulfuric acidconcentrations were used (columns 1-6 vs. columns 7-12), seven wellswere tested for each combination of test compound concentration andagonist solution (e.g., wells A1, B1, C1, E1, F1, G1, and Hi were testedfor test compound concentration 0.977 nM and agonist solution withsulfuric acid solution X mM). The wells in row D did not include anantagonist in order to measure the maximal Ca²⁺ response.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Compounds of Formula I

The invention encompasses compounds of formula I:

or a pharmaceutically acceptable derivative thereof, where W, X, Ar₁,Ar₂, R₃, R₄, R₂₀, and m are as defined above for compounds of formula I.

Certain embodiments of formula I are presented below.

In one embodiment, a compound of formula I is a pharmaceuticallyacceptable derivative of a compound of formula I.

In another embodiment, a compound of formula I is a compound of formulaI wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, a compound of formula I is a pharmaceuticallyacceptable salt of a compound of formula I.

In another embodiment, Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is pyridazinyl group.

In another embodiment, W is C.

In another embodiment, W is N.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, n or p is 1.

In another embodiment, n or p is 2.

In another embodiment, n is 3.

In another embodiment, m is 2.

In another embodiment, each R₃ is independently —H, or —(C₁-C₆)alkyl.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted, which bridge optionally contains —HC═CH— withinthe (C₂-C₃)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted, andwhich bridge joins positions 2 and 6 of the piperidine,1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a —CH₂—N(R_(a))—CH₂—bridge (B1), a

wherein R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b)-phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups; and

each R_(c) is independently —H or —(C₁-C₄)alkyl.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,—(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—S(O)₂—N(R_(c))₂, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c).

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,or —(CH₂)—C(O)—N(R_(c))₂.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is —H, —(C₃-C₈)cycloalkyl, or -(3- to7-membered)heterocycle.

In another embodiment, R_(b) is —H, —N(R_(c))₂,—N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to 7-membered)heterocycle.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is -phenyl or —N(R_(c))-phenyl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups.

In another embodiment, R_(b) is -(5- or 6-membered)heteroaryl or—N(R_(c))-(5- to 10-membered)heteroaryl, each of which is unsubstitutedor substituted with 1, 2 or 3 independently selected R₇ groups.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, -phenyl, or -(5- or6-membered)heteroaryl.

In another embodiment, R_(a) and R_(b) are each independently —H or—(C₁-C₆)alkyl.

In another embodiment, R_(a) and R_(b) are —CH₃.

In another embodiment, each R_(e) is independently —H or —CH₃.

In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups form a bicyclo group to give one ofthe following structures

In another embodiment, m is 1.

In another embodiment, m is 0.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, Ar₁ is a pyridyl group and n is 1.

In another embodiment, Ar₁ is a pyrazinyl group and p is 1.

In another embodiment, Ar₁ is a pyrimidinyl group and p is 1.

In another embodiment, Ar₁ is a pyridazinyl group and p is 1.

In another embodiment, when n and p are 1, then R₂ must be Q.

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, J is —OR₂₀, —SR₂₀ or —N(R₂₀)₂.

In another embodiment, J is —OR₂₀.

In another embodiment, J is —OH.

In another embodiment, J is —CN.

In another embodiment, Z₁ is —H.

In another embodiment, Z₁ is —OH.

In another embodiment, Z₁ is —OCH₃.

In another embodiment, Z₁ is —CH₂OH.

In another embodiment, Z₂ is —CH₂—OR₇.

In another embodiment, Z₂ is —CH₂OH.

In another embodiment, Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -phenyl, or -halo.

In another embodiment, Z₂ is —H.

In another embodiment, Z₂ is —CH₃.

In another embodiment, Z₃ is —H.

In another embodiment, Z₃ is —CH₃.

In another embodiment, Z₄ is —H.

In another embodiment, Z₄ is —(C₁-C₆)alkyl.

In another embodiment, Z₄ is —N(R₂₀)₂.

In another embodiment Z₄ is —OR₂₀.

In another embodiment, Z₄ is —OH.

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, m is 1 and R₃ is —(C₁-C₆)alkyl.

In another embodiment, m is 1 and R₃ is —CH₃ or —CH₂CH₃.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is —CH₂OH.

In another embodiment, m is 0.

In another embodiment, R₄ is —OH.

In another embodiment, R₄ is —OCF₃

In another embodiment, R₄ is -halo.

In another embodiment, R₄ is —F.

In another embodiment, R₄ is —C1.

In another embodiment, R₄ is —(C₁-C₆)alkyl.

In another embodiment, R₄ is —CH₃.

In another embodiment, R₄ is —CH₂OH.

In another embodiment, R₄ is —CH₂Cl.

In another embodiment, R₄ is —CH₂Br.

In another embodiment, R₄ is —CH₂I.

In another embodiment, R₄ is —CH₂F.

In another embodiment, R₄ is —CH(halo)₂.

In another embodiment, R₄ is —CF₃.

In another embodiment, R₄ is —NO₂.

In another embodiment, R₄ is —OR₁₀.

In another embodiment, R₄ is —SR₁₀.

In another embodiment, R₄ is —C(O)R₁₀.

In another embodiment, R₄ is —COOH.

In another embodiment, R₄ is —C(O)H.

In another embodiment, R₄ is —COOR₁₀.

In another embodiment, R₄ is —OC(O)R₁₀.

In another embodiment, R₄ is —SO₂R₁₀.

In another embodiment, R₄ is —OC(O)NHR₁₀.

In another embodiment, R₄ is —NHC(O)R₁₃.

In another embodiment, R₄ is —CON(R₁₃)₂.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is not —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is -halo.

In another embodiment, Ar₂ is

is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, Ar₂ is

is 2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, the invention encompasses compounds of formulaI.4:

or a pharmaceutically acceptable salt thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

C is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C, N, or O;

wherein no more than one of Y₁, Y₂, or Y₃ can be O, and for each Y₁, Y₂,and Y₃ that is N,

the N is bonded to one R₂₁ group, and for each Y₁, Y₂, and Y₃ that is C,the C is bonded to two R₂₀ groups, provided that there are no more thana total of two (C₁-C₆)alkyl groups substituted on all of Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, -(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or-halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —NR₂₀;

J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, then Z₂ is not -halo;

each R₃ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, or two R₃ groups form a bicyclo group to        give one of the following structures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ are independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H or —(C₁-C₆)alkyl;

each R₂₁ is independently —H, —(C₁-C₆)alkyl,

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2;

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

In another embodiment relating to formula I.4, E is ═O, ═S,═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, or ═N—OR₂₀.

In another embodiment relating to formula I.4, E is ═O, ═S, or ═N—OR₂₀.

In another embodiment, the invention encompasses compounds of formulaI.3:

or a pharmaceutically acceptable salt thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C or N;

wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R₂₀group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, -(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or-halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —NR₂₀;

J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, then Z₂ is not -halo;

each R₃ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, or two R₃ groups form a bicyclo group to        give one of the following structures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ are independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H or —(C₁-C₆)alkyl;

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2;

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

In another embodiment relating to formula I.3, E is ═O, ═S,═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, or ═N—OR₂₀.

In another embodiment relating to formula I.3, E is ═O, ═S, or ═N—OR₂₀.

In another embodiment, the invention encompasses compounds of formulaI.2:

or a pharmaceutically acceptable salt thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C or N;

wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R₂₀group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, —(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or-halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —NR₂₀;

J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, then Z₂ is not -halo;

each R₃ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, or two R₃ groups form a bicyclo group to        give one of the following structures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ are independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H or —(C₁-C₆)alkyl;

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2;

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

In another embodiment relating to formula I.2, E is ═O, ═S,═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, or ═N—OR₂₀.

In another embodiment relating to formula I.2, E is ═O, ═S, or ═N—OR₂₀.

In another embodiment, the invention encompasses compounds of formulaI.1:

or a pharmaceutically acceptable salt thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C or N;

wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R₂₀group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, -(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or-halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —NR₂₀;

J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, Z₂ in not -halo;

each R₃ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, or two R₃ groups may form bicyclo group,        which gives the following structures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ are independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H or —(C₁-C₆)alkyl;

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2;

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

In another embodiment relating to formula I.1, E is ═O, ═S,═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, or ═N—OR₂₀.

In another embodiment relating to formula I.1, E is ═O, ═S, or ═N—OR₂₀.

In other embodiments, the compound of formula I is

Other compounds of interest include

Aqueous solubility of compounds is often a desirable feature. Forexample, aqueous solubility of a compound permits that compound to bemore easily formulated into a variety of dosage forms that may beadministered to an animal. When a compound is not fully soluble in theblood, it may precipitate in the blood, and the animal's exposure to thedrug will accordingly not correspond to the administered dose. Aqueoussolubility increases the likelihood that a compound will not precipitatein an animal's blood, and increases the ability to predict exposure atthe target sight of the compound.

Compounds of formula I are highly soluble in aqueous solution. Forexample, at either pH 6.8 or pH 1.2, compound 200 is insoluble inaqueous solution, i.e., has an aqueous solubility <0.1 μM. In contrast,the aqueous solubility at pH 6.8, in μM, of compounds of formula I F2,E6, F6, and G2 is 3.0, 9.0, 9.2, and 38.2, respectively. The aqueoussolubility at pH 1.2, in μM, of compounds of formula I F2, E6, F6 and G2is 1.0, 27.2, >50 and >50, respectively. Additionally, the aqueoussolubility at either pH 6.8 or pH 1.2 of each of compounds of formula IG6, H6, J2, and Z1 is >50 μM. The following compounds are aqueousinsoluble at pH 6.8: 203, 207, 200, and 208. The following compoundshave very low aqueous solubility at pH 6.8: 209, 210, 211, 212, 213,214, and 215 have aqueous solubility, in μM, of 1.0, 0.4, 0.4, 1.9, 0.8,1.8, and 0.6, respectively. The aqueous solubility, in μM, at pH 1.2 ofcompounds 209, 210, 211, 212, 213, 214 and 215 is 9.3, 2.0, 1.3, 10.3,39.6, >50 and 9.6, respectively. In contrast, the aqueous solubility atpH 6.8, in μM, of compounds of formula I N1, F1, C1, Y3, and U3 is 28.0,22.6, 15.7, 17.4, and 26.4, respectively. At pH 1.2, compounds offormula I N1, F1, C1, Y3 and U3 all have an aqueous solubility of >50μM. The aqueous solubility, at either pH 6.8 or pH 1.2, is >50 μM foreach of the following compounds of formula I: H1, N6, Z1, S1, E2, andU1.

5.2 Compounds of Formula IA

Preferred compounds of formula I are compounds of formula IA:

or a pharmaceutically acceptable derivative thereof, where W, X, Ar₁,Ar₂, R₃, R₄, R₂₀, and m are as defined above for compounds of formulaIA.

Certain embodiments of formula IA are presented below.

In one embodiment, a compound of formula IA is a pharmaceuticallyacceptable derivative of a compound of formula IA.

In another embodiment, a compound of formula IA is a compound of formulaIA wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, a compound of formula IA is a pharmaceuticallyacceptable salt of a compound of formula IA.

In another embodiment, Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is pyridazinyl group.

In another embodiment, W is C.

In another embodiment, W is N.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, n or p is 1.

In another embodiment, n or p is 2.

In another embodiment, n is 3.

In another embodiment, m is 2.

In another embodiment, each R₃ is independently —H, or —(C₁-C₆)alkyl.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted, which bridge optionally contains —HC═CH— withinthe (C₂-C₃)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted, andwhich bridge joins positions 2 and 6 of the piperidine,1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a —CH₂—N(R_(a))—CH₂—bridge (B1), a

wherein R_(a), is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,—CH₂—C(O)—R_(c), —(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups; and

each R_(c) is independently —H or —(C₁-C₄)alkyl.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,—(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—S(O)₂—N(R_(c))₂, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c).

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,or —(CH₂)—C(O)—N(R_(c))₂.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is —H, —(C₃-C₈)cycloalkyl, or -(3- to7-membered)heterocycle.

In another embodiment, R_(b) is —H, —N(R_(c))₂,—N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to 7-membered)heterocycle.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is -phenyl or —N(R_(c))-phenyl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups.

In another embodiment, R_(b) is -(5- or 6-membered)heteroaryl or—N(R_(c))-(5- to 10-membered)heteroaryl, each of which is unsubstitutedor substituted with 1, 2 or 3 independently selected R₇ groups.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, -phenyl, or -(5- or6-membered)heteroaryl.

In another embodiment, R_(a) and R_(b) are each independently —H or—(C₁-C₆)alkyl.

In another embodiment, R_(a) and R_(b) are —CH₃.

In another embodiment, each R_(e) is independently —H or —CH₃.

In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups form a bicyclo group to give one ofthe following structures

In another embodiment, m is 1.

In another embodiment, m is 0.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, Ar₁ is a pyridyl group and n is 1.

In another embodiment, Ar₁ is a pyrazinyl group and p is 1.

In another embodiment, Ar₁ is a pyrimidinyl group and p is 1.

In another embodiment, Ar₁ is a pyridazinyl group and p is 1.

In another embodiment, when n and p are 1, then R₂ must be Q.

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, J is —OR₂₀, —SR₂₀ or —N(R₂₀)₂.

In another embodiment, J is —OR₂₀.

In another embodiment, J is —OH.

In another embodiment, J is —CN.

In another embodiment, Z₁ is —H.

In another embodiment, Z₁ is —OH.

In another embodiment, Z₁ is —OCH₃.

In another embodiment, Z₁ is —CH₂OH.

In another embodiment, Z₂ is —CH₂—OR₇.

In another embodiment, Z₂ is —CH₂OH.

In another embodiment, Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -phenyl, or -halo.

In another embodiment, Z₂ is —H.

In another embodiment, Z₂ is —CH₃.

In another embodiment, Z₃ is —H.

In another embodiment, Z₃ is —CH₃.

In another embodiment, Z₄ is —H.

In another embodiment, Z₄ is —(C₁-C₆)alkyl.

In another embodiment, Z₄ is —N(R₂₀)₂.

In another embodiment Z₄ is —OR₂₀.

In another embodiment, Z₄ is —OH.

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, Q is

In another embodiment, m is 1 and R₃ is —(C₁-C₆)alkyl.

In another embodiment, m is 1 and R₃ is —CH₃ or —CH₂CH₃.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is —CH₂OH.

In another embodiment, m is 0.

In another embodiment, R₄ is —OH.

In another embodiment, R₄ is —OCF₃

In another embodiment, R₄ is -halo.

In another embodiment, R₄ is —F.

In another embodiment, R₄ is —C1.

In another embodiment, R₄ is —(C₁-C₆)alkyl.

In another embodiment, R₄ is —CH₃.

In another embodiment, R₄ is —CH₂OH.

In another embodiment, R₄ is —CH₂C1.

In another embodiment, R₄ is —CH₂Br.

In another embodiment, R₄ is —CH₂I.

In another embodiment, R₄ is —CH₂F.

In another embodiment, R₄ is —CH(halo)₂.

In another embodiment, R₄ is —CF₃.

In another embodiment, R₄ is —NO₂.

In another embodiment, R₄ is —OR₁₀.

In another embodiment, R₄ is —SR₁₀.

In another embodiment, R₄ is —C(O)R₁₀.

In another embodiment, R₄ is —COOH.

In another embodiment, R₄ is —C(O)H.

In another embodiment, R₄ is —COOR₁₀.

In another embodiment, R₄ is —OC(O)R₁₀.

In another embodiment, R₄ is —SO₂R₁₀.

In another embodiment, R₄ is —OC(O)NHR₁₀.

In another embodiment, R₄ is —NHC(O)R₁₃.

In another embodiment, R₄ is —CON(R₁₃)₂.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is not —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is -halo.

In another embodiment, Ar₂ is

s is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, Ar₂ is

s is 2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OR₂₀.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OR₂₀ and Z₁ is —OR₇.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OR₂₀ and Z₁ is —CH₂OR₇.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein Z₄ is —OR₂₀.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OH.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OH and Z₁ is —OH.

In another embodiment, R₄ is -halo, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OH and Z₁ is —CH₂OH.

In another embodiment, R₄ is —F, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OH and Z₁ is —OH.

In another embodiment, R₄ is —F, n or p is 1, R₂ is Q, wherein Q is

wherein J is —OH and Z₁ is —CH₂OH.

In another embodiment, R₁ is -halo, R₄ is -halo, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀.

In another embodiment, R₁ is -halo, R₄ is -halo, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀ and Z₁ is —OR₇.

In another embodiment, R₁ is -halo, R₄ is -halo, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀ and Z₁ is —CH₂OR₇.

In another embodiment, R₁ is -halo, R₄ is -halo, n or p is 1, R₂ is Q,wherein Q is

wherein Z₄ is —OR₂₀.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀ and Z₁ is —OR₇.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OR₂₀ and Z₁ is —CH₂OR₇.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein Z₄ is —OR₂₀.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OH.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OH and Z₁ is —OH.

In another embodiment, R₁ is —Cl, R₄ is —F, n or p is 1, R₂ is Q,wherein Q is

wherein J is —OH and Z₁ is —CH₂OH.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, and R₂ isQ.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein J is —OH.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein J is —OR₂₀, and Z₁ is —OR₇.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein J is —OH, and Z₁ is —OH.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein J is —OR₂₀, and Z₁ is —CH₂OR₇.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein J is —OH, and Z₁ is —CH₂OH.

In another embodiment, Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q,and Q is

wherein Z₄ is —OR₂₀.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OR₂₀, Z₁ is —OR₇.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OR₂₀, Z₁ is —CH₂OR₇.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is benzothiazolyl, wherein at least oneof R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzothiazolyl, wherein at leastone of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is benzooxazolyl, wherein at least oneof R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzooxazolyl, wherein at leastone of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is benzoimidazolyl, wherein at leastone of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzoimidazolyl, wherein at leastone of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is phenyl, wherein s is 0 or 1.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is phenyl, wherein s is 0 or 1.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is phenyl, wherein s is 2.

In another embodiment, R₁ is -halo, R₄ is -halo, and Ar₁ is a pyridylgroup, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is phenyl, wherein s is 2.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OR₂₀.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OR₂₀ and Z₁ is —OR₇.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OR₂₀ and Z₁ is —CH₂OR₇.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein Z₄ is —OR₂₀.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OH.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OH and Z₁ is —OH.

In another embodiment, the dashed line is a double bond, n or p is 1, R₂is Q, wherein Q is

wherein J is —OH and Z₁ is —CH₂OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo, nor p is 1, R₂ is Q, wherein Q is

wherein J is —OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo, nor p is 1, R₂ is Q,

wherein Q is

wherein J is —OH and Z₁ is —OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo, nor p is 1, R₂ is Q, wherein Q is

wherein J is —OH and Z₁ is —CH₂OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH Ar₂ is benzothiazolyl, wherein at least oneof R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzothiazolyl, wherein at leastone of R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, and Q is

wherein J is —OH, Z₁ is —OH Ar₂ is benzooxazolyl, wherein at least oneof R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzooxazolyl, wherein at leastone of R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH, Ar₂ is benzoimidazolyl, wherein at leastone of R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is benzoimidazolyl, wherein at leastone of R₈ or R₉ is not a —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH Ar₂ is phenyl, wherein s is 0 or 1 and R₁₄is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇,or —SO₂C(halo)₃, and optionally is —F, —Cl, —CF₃, or —OCF₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is phenyl, wherein s is 0 or 1 andR₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇, —N(R₇)₂,—SO₂R₇, or —SO₂C(halo)₃, and optionally is —F, —Cl, —CF₃, or —OCF₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —OH Ar₂ is phenyl, wherein s is 2, and each R₁₄is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃, and optionally is —F, —Cl, —CF₃, or—OCF₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,and Ar₁ is a pyridyl group, wherein n is 1, R₂ is Q, and Q is

wherein J is —OH, Z₁ is —CH₂OH, Ar₂ is phenyl, wherein s is 2, and eachR₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃, and optionally is —F, —Cl, —CF₃, or—OCF₃.

In another embodiment Q is

wherein the compound of formula IA is racemic.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 60%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 70%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 80%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 90%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 99%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 60%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 70%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 80%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 90%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 99%.

In another embodiment, the invention encompasses compounds of formulaIA.1:

or a pharmaceutically acceptable salt thereof, where

X is O, S, N—CN, N—OH, or N—OR₁₀;

W is N or C;

the dashed line denotes the presence or absence of a bond, and when thedashed line denotes the presence of a bond or W is N then R₄ is absent,otherwise R₄ is —H, —OH, —OCF₃, -halo, —(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH, —COOR₁₀,—C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —CON(R₁₃)₂,—S(O)₂R₁₀, or —NO₂;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl;

Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2;

Y₁, Y₂, and Y₃ are independently C or N;

wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R₂₀group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃;

R_(12a) and R_(12b) are independently —H or —(C₁-C₆)alkyl;

E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, -(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or    -   (b) a group of formula Q;

wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or-halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or —NR₂₀;

J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂;

provided that at least one R₂ group is a group of formula Q, andprovided that when Z₁ is —OR₇ or —SR₇, Z₂ in not -halo;

each R₃ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, or two R₃ groups may form bicyclo group,        which gives the following structures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂;

each R₈ and R₉ are independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, or —OC(O)OR₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂;

each R₂₀ is independently —H or —(C₁-C₆)alkyl;

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2, or 3;

p is the integer 1 or 2;

each b is independently the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3; and

m is the integer 0, 1, or 2.

In another embodiment relating to formula IA.1, E is ═O, ═S,═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl, or ═N—OR₂₀.

In another embodiment relating to formula IA.1, E is ═O, ═S, or ═N—OR₂₀.

In another embodiment relating to formula IA.1, Q is

In another embodiment relating to formula IA.1, Q is

In another embodiment relating to formula IA.1, Q is

In another embodiment relating to formula IA.1, Q is

In another embodiment relating to formula IA.1, Q is

In another embodiment relating to formula IA.1, Q is

5.3 Compounds of Formula II

Preferred compounds of formula I are compounds of formula II:

or a pharmaceutically acceptable derivative thereof, where the dashedline, W, X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above forcompounds of formula I,

wherein Q is

Z₁ is —OH, —SH, —N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H, —CH₃, or —CH₂—OR₇;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

In addition to being highly soluble in aqueous solution, compounds offormula II are preferred because side effects are less severe (e.g.,attenuation or removal of central nervous system side effects) inanimals administered a compound of formula II. For example, musclerelaxation is attenuated or absent in animals administered a compound offormula II. Sedation is attenuated or absent in animals administered acompound of formula II. Ataxia is attenuated or absent in animalsadministered a compound of formula II. Flat body posture is attenuatedor absent in animals administered a compound of formula II. Tremor isattenuated or absent in animals administered a compound of formula II.When a compound induces less severe side effects, the therapeutic index,which is the difference between an effective dose and a dose that causesadverse effects, is increased. Therapeutic index is a measure of thesafety of a compound when administered to an animal. The greater thetherapeutic index, the safer the compound.

Compounds of formula II also have excellent pharmacokinetic properties.Specifically, the plasma level of a compound of formula II in an animalis dose proportionate. Therefore, the amount of compound in the plasmaof an animal can be more readily controlled according to the dose of thecompound administered to the animal. Moreover, for a given doseadministered, the animal plasma concentration is greater and is achievedmore rapidly for a compound of formula II. For example, compound 200achieves its maximum plasma concentration 3.1 h after administration. Incontrast, compound of formula II Z1 achieves its maximum plasmaconcentration 2.5 h after administration and that maximum plasmaconcentration is 2.5 times greater than the maximum for compound 200.Additionally, compound of formula II R6 achieves its maximum plasmaconcentration 1.85 h after administration and that maximum plasmaconcentration is 5.3 times greater than the maximum for compound 200.For each of compounds of formula II Z1 and R6, the plasma concentrationup to 24 h is consistently greater for each when compared with compound200.

Compounds of formula II are also preferred because they have a hightherapeutic index. Therapeutic index is the difference between theamount of a compound that is effective for treating a Condition and theamount of that same compound that induces adverse effects.

Other embodiments of formula II are presented below.

In one embodiment, a compound of formula II is a pharmaceuticallyacceptable derivative of a compound of formula II.

In another embodiment, a compound of formula I is a compound of formulaII wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, a compound of formula II is a pharmaceuticallyacceptable salt of a compound of formula II.

In another embodiment, Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is pyridazinyl group.

In another embodiment, W is C.

In another embodiment, W is N.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, n or p is 1.

In another embodiment, n or p is 2.

In another embodiment, n is 3.

In another embodiment, m is 2.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted, which bridge optionally contains —HC═CH— withinthe (C₂-C₃)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted, andwhich bridge joins positions 2 and 6 of the piperidine,1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a —CH₂—N(R_(a))—CH₂—bridge (B1), a

wherein R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups; and

each R_(c) is independently —H or —(C₁-C₄)alkyl.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,—(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—S(O)₂—N(R_(c))₂, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c).

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,or —(CH₂)—C(O)—N(R_(c))₂.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is —H, —(C₃-C₈)cycloalkyl, or -(3- to7-membered)heterocycle.

In another embodiment, R_(b) is —H, —N(R_(c))₂,—N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to 7-membered)heterocycle.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is -phenyl or —N(R_(c))-phenyl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups.

In another embodiment, R_(b) is -(5- or 6-membered)heteroaryl or—N(R_(c))-(5- to 10-membered)heteroaryl, each of which is unsubstitutedor substituted with 1, 2 or 3 independently selected R₇ groups.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, -phenyl, or -(5- or6-membered)heteroaryl.

In another embodiment, R_(a) and R_(b) are each independently —H or—(C₁-C₆)alkyl.

In another embodiment, R_(a) and R_(b) are —CH₃.

In another embodiment, each R_(e) is independently —H or —CH₃.

In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups form a bicyclo group to give one ofthe following structures

In another embodiment, m is 1.

In another embodiment, m is 0.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, Ar₁ is a pyridyl group and n is 1.

In another embodiment, Ar₁ is a pyrazinyl group and p is 1.

In another embodiment, Ar₁ is a pyrimidinyl group and p is 1.

In another embodiment, Ar₁ is a pyridazinyl group and p is 1.

In another embodiment, Q is

In another embodiment, J is —OR₂₀.

In another embodiment, J is —OH.

In another embodiment, Z₁ is —OR₇.

In another embodiment, Z₁ is —OH.

In another embodiment, Z₁ is —CH₂—OR₇.

In another embodiment, Z₁ is —CH₂OH.

In another embodiment, Z₂ is —CH₂—OR₇.

In another embodiment, Z₂ is —CH₂OH.

In another embodiment, Z₂ is —H or —CH₃.

In another embodiment, Z₂ is —H.

In another embodiment, Z₂ is —CH₃.

In another embodiment, Z₃ is —H.

In another embodiment, Z₃ is —CH₃.

In another embodiment, m is 1 and R₃ is —(C₁-C₆)alkyl.

In another embodiment, m is 1 and R₃ is —CH₃ or —CH₂CH₃.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is —CH₂OH.

In another embodiment, R₄ is —OH.

In another embodiment, R₄ is —OCF₃

In another embodiment, R₄ is -halo.

In another embodiment, R₄ is —F.

In another embodiment, R₄ is —C1.

In another embodiment, R₄ is —(C₁-C₆)alkyl.

In another embodiment, R₄ is —CH₃.

In another embodiment, R₄ is —CH₂OH.

In another embodiment, R₄ is —CH₂Cl.

In another embodiment, R₄ is —CH₂Br.

In another embodiment, R₄ is —CH₂I.

In another embodiment, R₄ is —CH₂F.

In another embodiment, R₄ is —CH(halo)₂.

In another embodiment, R₄ is —CF₃.

In another embodiment, R₄ is —NO₂.

In another embodiment, R₄ is —OR₁₀.

In another embodiment, R₄ is —SR₁₀.

In another embodiment, R₄ is —C(O)R₁₀.

In another embodiment, R₄ is —COOH.

In another embodiment, R₄ is —C(O)H.

In another embodiment, R₄ is —COOR₁₀.

In another embodiment, R₄ is —OC(O)R₁₀.

In another embodiment, R₄ is —SO₂R₁₀.

In another embodiment, R₄ is —OC(O)NHR₁₀.

In another embodiment, R₄ is —NHC(O)R₁₃.

In another embodiment, R₄ is —CON(R₁₃)₂.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is independently —H or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is independently —(C₁-C₆)alkyl or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —(C₃-C₈)cycloalkyl.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is not —H.

In another embodiment, Ar₂ is a benzothiazolyl, benzoimidazolyl, orbenzooxazolyl group; and at least one of R₈ and R₉ is -halo.

In another embodiment, Ar₂ is

s is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, Ar₂ is

s is 2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, J is —OH, and Z₁ is —OH.

In another embodiment, J is —OH and Z₁ is —CH₂OH.

In another embodiment, J is —OH, Z₁ is —OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, J is —OH, Z₁ is —CH₂OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, R₄ is -halo, J is —OH, Z₁ is —OH, Z₂ is —H, andZ₃ is —H.

In another embodiment, R₄ is -halo, J is —OH, Z₁ is —CH₂OH, Z₂ is —H,and Z₃ is —H.

In another embodiment, R₄ is —F, J is —OH, Z₁ is —OH, Z₂ is —H, and Z₃is —H.

In another embodiment, R₄ is —F, J is —OH, Z₁ is —CH₂OH, Z₂ is —H, andZ₃ is —H.

In another embodiment, R₁ is -halo, R₄ is -halo, J is —OH, Z₁ is —OH, Z₂is —H, and Z₃ is —H.

In another embodiment, R₁ is -halo, R₄ is -halo, J is —OH, Z₁ is —CH₂OH,Z₂ is —H, and Z₃ is —H.

In another embodiment, R₁ is —Cl, R₄ is —F, J is —OH, Z₁ is —OH, Z₂ is—H, and Z₃ is —H.

In another embodiment, R₁ is —Cl, R₄ is —F, J is —OH, Z₁ is —CH₂OH, Z₂is —H, and Z₃ is —H.

In another embodiment Ar₁ is

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzooxazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzooxazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzothiazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzothiazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzoimidazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzoimidazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is,

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is 1.

In another embodiment, R₁ is -halo, R₄ is -halo, Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is2.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, and Z₃ is —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzooxazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzooxazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzothiazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzothiazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzoimidazolyl, whereinat least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is benzoimidazolyl,wherein at least one of R₈ or R₉ is not —H.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is 1.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is 2.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is1.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is2.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is 1,and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇, —N(R₇)₂,—SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is1, and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is 2,and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment, the dashed line is a double bond, R₁ is -halo,Ar₁ is

J is —OH, Z₁ is —CH₂OH, Z₂ is —H, Z₃ is —H, Ar₂ is phenyl, wherein s is2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —SO₂R₇, or —SO₂C(halo)₃.

In another embodiment Q is

wherein the compound of formula II is racemic.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 60%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 70%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 80%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 90%.

In another embodiment Q is

wherein the % ee of the R enantiomer is greater than 99%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 60%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 70%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 80%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 90%.

In another embodiment Q is

wherein the % ee of the S enantiomer is greater than 99%.

In another embodiment Q is

In another embodiment Q is

In another embodiment, the invention encompasses compounds formula II.4:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above for compounds offormula I.4,

wherein Q is

Z₁ is —OH, —SH, N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H or —CH₃;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

In another embodiment, the invention encompasses compounds formula II.3:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above for compounds offormula I.3,

wherein Q is

Z₁ is —OH, —SH, N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H or —CH₃;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

In another embodiment, the invention encompasses compounds formula II.2:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are as defined above for compounds offormula I.2,

wherein Q is

Z₁ is —OH, —SH, N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H or —CH₃;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

In another embodiment, the invention encompasses compounds formula II.1:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, R₂₀, and m are defined above for compounds offormula I.1,

wherein Q is

Z₁ is —OH, —SH, N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂;

Z₂ is —H or —CH₃;

each Z₃ is independently —H or —CH₃; and

J is —OH, —SH, or —N(R₂₀)₂.

5.4 Compounds of Formula III

Preferred compounds of formula II are compounds of formula III:

or a pharmaceutically acceptable derivative thereof, where the dashedline, W, X, R₃, R₄, and m are as defined above for compounds of formulaI,

wherein Ar₁ is:

R₁ is —Cl, —F, —CF₃, or —CH₃;

wherein Ar₂ is:

R₁₄ is —H, —Cl, —F, —Br, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is —H,—CF₃, —OCF₃, —Cl, or —F;

R_(14′) is —H, —Cl, —F, —Br, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is —H,—CF₃, —OCF₃, —Cl, or —F; and

each R₈ and R₉ is independently —H, —Cl, —Br, —F, —CH₃, —OCH₃, —OCH₂CH₃,—CF₃, —OCF₃, iso-propyl, or tert-butyl.

In addition to being highly soluble in aqueous solution at both pH 6.8and pH 1.2, having a very high therapeutic index, and having excellentpharmacokinetic parameters as described for formulae I and II, compoundsof formula III are preferred because they are also very bioavailable,and are believed to be highly efficacious in animals for the treatmentof pain. Bioavailability is a measure of how much of the doseadministered reaches systemic circulation after oral administration. Forexample, compounds of formula III R6 and G1 are 68.9% and 70.7%bioavailable following oral administration, respectively. The compoundof formula III D2 produced a 78.7% maximum reversal of FCA-inducedhyperalgesia at 5 hours post-administration, with an ED₅₀ of 1.63 mg/kg.

Certain embodiments of formula III are presented below.

In one embodiment, a compound of formula III is a pharmaceuticallyacceptable derivative of a compound of formula III.

In another embodiment, a compound of formula I is a compound of formulaIII wherein the derivative is a pharmaceutically acceptable salt.

In another embodiment, a compound of formula III is a pharmaceuticallyacceptable salt of a compound of formula III.

In another embodiment, Ar₁ is:

In a preferred embodiment, Ar₁ is:

In another embodiment, m is 2.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, which bridge optionally contains —HC═CH— within the(C₂-C₆)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge, and which bridgejoins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine orpiperazine ring.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted, which bridge optionally contains —HC═CH— withinthe (C₂-C₃)bridge, and which bridge joins positions 2 and 6 of thepiperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted, andwhich bridge joins positions 2 and 6 of the piperidine,1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups together form a —CH₂—N(R_(a))—CH₂—bridge (B1), a

wherein R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b)-phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₇ groups; and

each R_(c) is independently —H or —(C₁-C₄)alkyl.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,—(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—S(O)₂—N(R_(c))₂, or—(CH₂)₂—N(R_(c))S(O)₂—R_(c).

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl,or —(CH₂)—C(O)—N(R_(c))₂.

In another embodiment, R_(a) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is —H, —(C₃-C₈)cycloalkyl, or -(3- to7-membered)heterocycle.

In another embodiment, R_(b) is —H, —N(R_(c))₂,—N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to 7-membered)heterocycle.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, or—(C₃-C₈)cycloalkyl.

In another embodiment, R_(b) is -phenyl or —N(R_(c))-phenyl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups.

In another embodiment, R_(b) is -(5- or 6-membered)heteroaryl or—N(R_(c))-(5- to 10-membered)heteroaryl, each of which is unsubstitutedor substituted with 1, 2 or 3 independently selected R₇ groups.

In another embodiment, R_(b) is —H, —(C₁-C₆)alkyl, -phenyl, or -(5- or6-membered)heteroaryl.

In another embodiment, R_(a) and R_(b) are each independently —H or—(C₁-C₆)alkyl.

In another embodiment, R_(a) and R_(b) are —CH₃.

In another embodiment, each R_(e) is independently —H or —CH₃.

In another embodiment, the B1, B2, or B3 bridge joins positions 2 and 6of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.

In another embodiment, two R₃ groups form a bicyclo group to give one ofthe following structures

In another embodiment, R₁ is —Cl, —F, or —CF₃.

In another embodiment, m is 1.

In another embodiment, m is 1 and R₃ is —CH₃ or —CH₂CH₃.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is —CH₂OH.

In another embodiment, m is 0.

In another embodiment X is O.

In another embodiment the dashed line denotes the presence of a bond andR₄ is absent.

In another embodiment W is N and R₄ is absent.

In another embodiment R₄ is —H, —OH, —Cl, or F.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment Ar₂ is

In another embodiment Ar₁ is

wherein the compound of formula III is racemic.

In another embodiment Ar₁ is

wherein the % ee of the R enantiomer is greater than 60%.

In another embodiment Ar₁ is

wherein the % ee of the R enantiomer is greater than 70%.

In another embodiment Ar₁ is

wherein the % ee of the R enantiomer is greater than 80%.

In another embodiment Ar₁ is

wherein the % ee of the R enantiomer is greater than 90%.

In another embodiment Ar₁ is

wherein the % ee of the R enantiomer is greater than 99%.

In another embodiment Ar₁ is

wherein the % ee of the S enantiomer is greater than 60%.

In another embodiment Ar₁ is

wherein the % ee of the S enantiomer is greater than 70%.

In another embodiment Ar₁ is

wherein the % ee of the S enantiomer is greater than 80%.

In another embodiment Ar₁ is

wherein the % ee of the S enantiomer is greater than 90%.

In another embodiment Ar₁ is

wherein the % ee of the S enantiomer is greater than 99%.

In another embodiment Ar₁ is

In another embodiment Ar₁ is

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment the compound of formula III is

or a pharmaceutically acceptable derivative thereof, where R₁₄ is asdefined above for the compounds of formula I.

In another embodiment, the invention encompasses compounds of formulaIII.4:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, and m are as defined above for compounds of formulaI.4,

wherein Ar₁ is:

R₁ is —Cl, —F, or —CF₃;

wherein Ar₂ is:

R_(14′) is —H, —Cl, —F, —Br, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃;

R₉ is —Cl, F, or CH₃.

In another embodiment, the invention encompasses compounds of formulaIII.3:

or a pharmaceutically acceptable salt thereof, where the dashed line, W,X, Ar₁, Ar₂, R₃, R₄, and m are as defined above for compounds of formulaI.3,

wherein Ar₁ is:

R₁ is —Cl, —F, or —CF₃;

wherein Ar₂ is:

R₁₄ is —Cl, —F, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃;

R₉ is —Cl, F, or CH₃.

Illustrative compounds of formula III are listed below in Tables 1-36:

TABLE 1 (IIIa)

Compound R₁ R_(14′) AAA —Cl —Cl AAB —Cl —F AAC —Cl —OCH₃ AAD —Cl—OCH₂CH₃ AAE —F —Cl AAF —F —F AAG —F —OCH₃ AAH —F —OCH₂CH₃ AAI —CF₃ —ClAAJ —CF₃ —F AAK —CF₃ —OCH₃ AAL —CF₃ —OCH₂CH₃

TABLE 2 (IIIb)

Compound R₁ R_(14′) AAM —Cl —Cl AAN —Cl —F AAO —Cl —OCH₃ AAP —Cl—OCH₂CH₃ AAQ —F —Cl AAR —F —F AAS —F —OCH₃ AAT —F —OCH₂CH₃ AAU —CF₃ —ClAAV —CF₃ —F AAW —CF₃ —OCH₃ AAX —CF₃ —OCH₂CH₃

TABLE 3 (IIIc)

Compound R₁ R_(14′) AAY —Cl —Cl AAZ —Cl —F ABA —Cl —OCH₃ ABB —Cl—OCH₂CH₃ ABC —F —Cl ABD —F —F ABE —F —OCH₃ ABF —F —OCH₂CH₃ ABG —CF₃ —ClABH —CF₃ —F ABI —CF₃ —OCH₃ ABJ —CF₃ —OCH₂CH₃

TABLE 4 (IIId)

Compound R₁ R_(14′) ABK —Cl —Cl ABL —Cl —F ABM —Cl —OCH₃ ABN —Cl—OCH₂CH₃ ABO —F —Cl ABP —F —F ABQ —F —OCH₃ ABR —F —OCH₂CH₃ ABS —CF₃ —ClABT —CF₃ —F ABU —CF₃ —OCH₃ ABV —CF₃ —OCH₂CH₃

TABLE 5 (IIIe)

Compound R₁ R_(14′) ABW —Cl —Cl ABX —Cl —F ABY —Cl —OCH₃ ABZ —Cl—OCH₂CH₃ ACA —F —Cl ACB —F —F ACC —F —OCH₃ ACD —F —OCH₂CH₃ ACE —CF₃ —ClACF —CF₃ —F ACG —CF₃ —OCH₃ ACH —CF₃ —OCH₂CH₃

TABLE 6 (IIIf)

Compound R₁ R_(14′) ACI —Cl —Cl ACJ —Cl —F ACK —Cl —OCH₃ ACL —Cl—OCH₂CH₃ ACM —F —Cl ACN —F —F ACO —F —OCH₃ ACP —F —OCH₂CH₃ ACQ —CF₃ —ClACR —CF₃ —F ACS —CF₃ —OCH₃ ACT —CF₃ —OCH₂CH₃

TABLE 7 (IIIg)

Compound R₁ R_(14′) BAA —Cl —CH₃ BAB —Cl —CH₂CH₃ BAC —Cl —Cl BAD —F —CH₃BAE —F —CH₂CH₃ BAF —F —Cl BAG —CF₃ —CH₃ BAH —CF₃ —CH₂CH₃ BAI —CF₃ —Cl

TABLE 8 (IIIh)

Compound R₁ R_(14′) BAJ —Cl —CH₃ BAK —Cl —CH₂CH₃ BAL —Cl —Cl BAM —F —CH₃BAN —F —CH₂CH₃ BAO —F —Cl BAP —CF₃ —CH₃ BAQ —CF₃ —CH₂CH₃ BAR —CF₃ —Cl

TABLE 9 (IIIi)

Compound R₁ R_(14′) BAS —Cl —CH₃ BAT —Cl —CH₂CH₃ BAU —Cl —Cl BAV —F —CH₃BAW —F —CH₂CH₃ BAX —F —Cl BAY —CF₃ —CH₃ BAZ —CF₃ —CH₂CH₃ BBA —CF₃ —Cl

TABLE 10 (IIIj)

Compound R₁ R_(14′) BBB —Cl —CH₃ BBC —Cl —CH₂CH₃ BBD —Cl —Cl BBE —F —CH₃BBF —F —CH₂CH₃ BBG —F —Cl BBH —CF₃ —CH₃ BBI —CF₃ —CH₂CH₃ BBJ —CF₃ —Cl

TABLE 11 (IIIk)

Compound R₁ R_(14′) BBK —Cl —CH₃ BBL —Cl —CH₂CH₃ BBM —Cl —Cl BBN —F —CH₃BBO —F —CH₂CH₃ BBP —F —Cl BBQ —CF₃ —CH₃ BBR —CF₃ —CH₂CH₃ BBS —CF₃ —Cl

TABLE 12 (IIIl)

Compound R₁ R_(14′) BBT —Cl —CH₃ BBU —Cl —CH₂CH₃ BBV —Cl —Cl BBW —F —CH₃BBX —F —CH₂CH₃ BBY —F —Cl BBZ —CF₃ —CH₃ BCA —CF₃ —CH₂CH₃ BCB —CF₃ —Cl

In other embodiments, substituent R_(14′) of Tables 1-12 can be H.

TABLE 13 (IIIm)

Compound R₁ CAA —Cl CAB —F CAC —CF₃

TABLE 14 (IIIn)

Compound R₁ CAD —Cl CAE —F CAF —CF₃

TABLE 15 (IIIo)

Compound R₁ CAG —Cl CAH —F CAI —CF₃

TABLE 16 (IIIp)

Compound R₁ CAJ —Cl CAK —F CAL —CF₃

TABLE 17 (IIIq)

Compound R₁ CAM —Cl CAN —F CAO —CF₃

TABLE 18 (IIIr)

Compound R₁ CAP —Cl CAQ —F CAR —CF₃

TABLE 19 (IIIs)

Compound R₁ DAA —Cl DAB —F DAC —CF₃

TABLE 20 (IIIt)

Compound R₁ DAD —Cl DAE —F DAF —CF₃

TABLE 21 (IIIu)

Compound R₁ DAG —Cl DAH —F DAI —CF₃

TABLE 22 (IIv)

Compound R₁ DAJ —Cl DAK —F DAL —CF₃

TABLE 23 (IIIw)

Compound R₁ DAM —Cl DAN —F DAO —CF₃

TABLE 24 (IIx)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁DAP —Cl DAQ —F DAR —CF₃

TABLE 25 (IIIy)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₉ EAA —Cl —Cl EAB —Cl —F EAC —Cl —CH₃ EAD —F —Cl EAE —F —F EAF —F —CH₃EAG —CF₃ —Cl EAH —CF₃ —F EAI —CF₃ —CH₃

TABLE 26 (IIIz)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₉ EAJ —Cl —Cl EAK —Cl —F EAL —Cl —CH₃ EAM —F —Cl EAN —F —F EAO —F —CH₃EAP —CF₃ —Cl EAQ —CF₃ —F EAR —CF₃ —CH₃

TABLE 27 (IIIaa) (IIIab)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₈ R₉ EAS1 aa or ab —Cl —H —H EAS2 aa or ab —Cl —H —Cl EAS3 aa or ab —Cl—H —Br EAS4 aa or ab —Cl —H —F EAS5 aa or ab —Cl —H —CH₃ EAS6 aa or ab—Cl —H —OCH₃ EAS7 aa or ab —Cl —H —OCH₂CH₃ EAS8 aa or ab —Cl —H —CF₃EAS9 aa or ab —Cl —H —OCF₃ EAS10 aa or ab —Cl —H iso-propyl EAS11 aa orab —Cl —H tert-butyl EAS12 aa or ab —Cl —Cl —H EAS13 aa or ab —Cl —Cl—Cl EAS14 aa or ab —Cl —Cl —Br EAS15 aa or ab —Cl —Cl —F EAS16 aa or ab—Cl —Cl —CH₃ EAS17 aa or ab —Cl —Cl —OCH₃ EAS18 aa or ab —Cl —Cl—OCH₂CH₃ EAS19 aa or ab —Cl —Cl —CF₃ EAS20 aa or ab —Cl —Cl —OCF₃ EAS21aa or ab —Cl —Cl iso-propyl EAS22 aa or ab —Cl —Cl tert-butyl EAS23 aaor ab —Cl —Br —H EAS24 aa or ab —Cl —Br —Cl EAS25 aa or ab —Cl —Br —BrEAS26 aa or ab —Cl —Br —F EAS27 aa or ab —Cl —Br —CH₃ EAS28 aa or ab —Cl—Br —OCH₃ EAS29 aa or ab —Cl —Br —OCH₂CH₃ EAS30 aa or ab —Cl —Br —CF₃EAS31 aa or ab —Cl —Br —OCF₃ EAS32 aa or ab —Cl —Br iso-propyl EAS33 aaor ab —Cl —Br tert-butyl EAS34 aa or ab —Cl —F —H EAS35 aa or ab —Cl —F—Cl EAS36 aa or ab —Cl —F —Br EAS37 aa or ab —Cl —F —F EAS38 aa or ab—Cl —F —CH₃ EAS39 aa or ab —Cl —F —OCH₃ EAS40 aa or ab —Cl —F —OCH₂CH₃EAS41 aa or ab —Cl —F —CF₃ EAS42 aa or ab —Cl —F —OCF₃ EAS43 aa or ab—Cl —F iso-propyl EAS44 aa or ab —Cl —F tert-butyl EAS45 aa or ab —Cl—CH₃ —H EAS46 aa or ab —Cl —CH₃ —Cl EAS47 aa or ab —Cl —CH₃ —Br EAS48 aaor ab —Cl —CH₃ —F EAS49 aa or ab —Cl —CH₃ —CH₃ EAS50 aa or ab —Cl —CH₃—OCH₃ EAS51 aa or ab —Cl —CH₃ —OCH₂CH₃ EAS52 aa or ab —Cl —CH₃ —CF₃EAS53 aa or ab —Cl —CH₃ —OCF₃ EAS54 aa or ab —Cl —CH₃ iso-propyl EAS55aa or ab —Cl —CH₃ tert-butyl EAS56 aa or ab —Cl —OCH₃ —H EAS57 aa or ab—Cl —OCH₃ —Cl EAS58 aa or ab —Cl —OCH₃ —Br EAS59 aa or ab —Cl —OCH₃ —FEAS60 aa or ab —Cl —OCH₃ —CH₃ EAS61 aa or ab —Cl —OCH₃ —OCH₃ EAS62 aa orab —Cl —OCH₃ —OCH₂CH₃ EAS63 aa or ab —Cl —OCH₃ —CF₃ EAS64 aa or ab —Cl—OCH₃ —OCF₃ EAS65 aa or ab —Cl —OCH₃ iso-propyl EAS66 aa or ab —Cl —OCH₃tert-butyl EAS67 aa or ab —Cl —OCH₂CH₃ —H EAS68 aa or ab —Cl —OCH₂CH₃—Cl EAS69 aa or ab —Cl —OCH₂CH₃ —Br EAS70 aa or ab —Cl —OCH₂CH₃ —F EAS71aa or ab —Cl —OCH₂CH₃ —CH₃ EAS72 aa or ab —Cl —OCH₂CH₃ —OCH₃ EAS73 aa orab —Cl —OCH₂CH₃ —OCH₂CH₃ EAS74 aa or ab —Cl —OCH₂CH₃ —CF₃ EAS75 aa or ab—Cl —OCH₂CH₃ —OCF₃ EAS76 aa or ab —Cl —OCH₂CH₃ iso-propyl EAS77 aa or ab—Cl —OCH₂CH₃ tert-butyl EAS78 aa or ab —Cl —CF₃ —H EAS79 aa or ab —Cl—CF₃ —Cl EAS80 aa or ab —Cl —CF₃ —Br EAS81 aa or ab —Cl —CF₃ —F EAS82 aaor ab —Cl —CF₃ —CH₃ EAS83 aa or ab —Cl —CF₃ —OCH₃ EAS84 aa or ab —Cl—CF₃ —OCH₂CH₃ EAS85 aa or ab —Cl —CF₃ —CF₃ EAS86 aa or ab —Cl —CF₃ —OCF₃EAS87 aa or ab —Cl —CF₃ iso-propyl EAS88 aa or ab —Cl —CF₃ tert-butylEAS89 aa or ab —Cl —OCF₃ —H EAS90 aa or ab —Cl —OCF₃ —Cl EAS91 aa or ab—Cl —OCF₃ —Br EAS92 aa or ab —Cl —OCF₃ —F EAS93 aa or ab —Cl —OCF₃ —CH₃EAS94 aa or ab —Cl —OCF₃ —OCH₃ EAS95 aa or ab —Cl —OCF₃ —OCH₂CH₃ EAS96aa or ab —Cl —OCF₃ —CF₃ EAS97 aa or ab —Cl —OCF₃ —OCF₃ EAS98 aa or ab—Cl —OCF₃ iso-propyl EAS99 aa or ab —Cl —OCF₃ tert-butyl EAS100 aa or ab—Cl iso-propyl —H EAS101 aa or ab —Cl iso-propyl —Cl EAS102 aa or ab —Cliso-propyl —Br EAS103 aa or ab —Cl iso-propyl —F EAS104 aa or ab —Cliso-propyl —CH₃ EAS105 aa or ab —Cl iso-propyl —OCH₃ EAS106 aa or ab —Cliso-propyl —OCH₂CH₃ EAS107 aa or ab —Cl iso-propyl —CF₃ EAS108 aa or ab—Cl iso-propyl —OCF₃ EAS109 aa or ab —Cl iso-propyl iso-propyl EAS110 aaor ab —Cl iso-propyl tert-butyl EAS111 aa or ab —Cl tert-butyl —H EAS112aa or ab —Cl tert-butyl —Cl EAS113 aa or ab —Cl tert-butyl —Br EAS114 aaor ab —Cl tert-butyl —F EAS115 aa or ab —Cl tert-butyl —CH₃ EAS116 aa orab —Cl tert-butyl —OCH₃ EAS117 aa or ab —Cl tert-butyl —OCH₂CH₃ EAS118aa or ab —Cl tert-butyl —CF₃ EAS119 aa or ab —Cl tert-butyl —OCF₃ EAS120aa or ab —Cl tert-butyl iso-propyl EAS121 aa or ab —Cl tert-butyltert-butyl EAT1 aa or ab —F —H —H EAT2 aa or ab —F —H —Cl EAT3 aa or ab—F —H —Br EAT4 aa or ab —F —H —F EAT5 aa or ab —F —H —CH₃ EAT6 aa or ab—F —H —OCH₃ EAT7 aa or ab —F —H —OCH₂CH₃ EAT8 aa or ab —F —H —CF₃ EAT9aa or ab —F —H —OCF₃ EAT10 aa or ab —F —H iso-propyl EAT11 aa or ab —F—H tert-butyl EAT12 aa or ab —F —Cl —H EAT13 aa or ab —F —Cl —Cl EAT14aa or ab —F —Cl —Br EAT15 aa or ab —F —Cl —F EAT16 aa or ab —F —Cl —CH₃EAT17 aa or ab —F —Cl —OCH₃ EAT18 aa or ab —F —Cl —OCH₂CH₃ EAT19 aa orab —F —Cl —CF₃ EAT20 aa or ab —F —Cl —OCF₃ EAT21 aa or ab —F —Cliso-propyl EAT22 aa or ab —F —Cl tert-butyl EAT23 aa or ab —F —Br —HEAT24 aa or ab —F —Br —Cl EAT25 aa or ab —F —Br —Br EAT26 aa or ab —F—Br —F EAT27 aa or ab —F —Br —CH₃ EAT28 aa or ab —F —Br —OCH₃ EAT29 aaor ab —F —Br —OCH₂CH₃ EAT30 aa or ab —F —Br —CF₃ EAT31 aa or ab —F —Br—OCF₃ EAT32 aa or ab —F —Br iso-propyl EAT33 aa or ab —F —Br tert-butylEAT34 aa or ab —F —F —H EAT35 aa or ab —F —F —Cl EAT36 aa or ab —F —F—Br EAT37 aa or ab —F —F —F EAT38 aa or ab —F —F —CH₃ EAT39 aa or ab —F—F —OCH₃ EAT40 aa or ab —F —F —OCH₂CH₃ EAT41 aa or ab —F —F —CF₃ EAT42aa or ab —F —F —OCF₃ EAT43 aa or ab —F —F iso-propyl EAT44 aa or ab —F—F tert-butyl EAT45 aa or ab —F —CH₃ —H EAT46 aa or ab —F —CH₃ —Cl EAT47aa or ab —F —CH₃ —Br EAT48 aa or ab —F —CH₃ —F EAT49 aa or ab —F —CH₃—CH₃ EAT50 aa or ab —F —CH₃ —OCH₃ EAT51 aa or ab —F —CH₃ —OCH₂CH₃ EAT52aa or ab —F —CH₃ —CF₃ EAT53 aa or ab —F —CH₃ —OCF₃ EAT54 aa or ab —F—CH₃ iso-propyl EAT55 aa or ab —F —CH₃ tert-butyl EAT56 aa or ab —F—OCH₃ —H EAT57 aa or ab —F —OCH₃ —Cl EAT58 aa or ab —F —OCH₃ —Br EAT59aa or ab —F —OCH₃ —F EAT60 aa or ab —F —OCH₃ —CH₃ EAT61 aa or ab —F—OCH₃ —OCH₃ EAT62 aa or ab —F —OCH₃ —OCH₂CH₃ EAT63 aa or ab —F —OCH₃—CF₃ EAT64 aa or ab —F —OCH₃ —OCF₃ EAT65 aa or ab —F —OCH₃ iso-propylEAT66 aa or ab —F —OCH₃ tert-butyl EAT67 aa or ab —F —OCH₂CH₃ —H EAT68aa or ab —F —OCH₂CH₃ —Cl EAT69 aa or ab —F —OCH₂CH₃ —Br EAT70 aa or ab—F —OCH₂CH₃ —F EAT71 aa or ab —F —OCH₂CH₃ —CH₃ EAT72 aa or ab —F—OCH₂CH₃ —OCH₃ EAT73 aa or ab —F —OCH₂CH₃ —OCH₂CH₃ EAT74 aa or ab —F—OCH₂CH₃ —CF₃ EAT75 aa or ab —F —OCH₂CH₃ —OCF₃ EAT76 aa or ab —F—OCH₂CH₃ iso-propyl EAT77 aa or ab —F —OCH₂CH₃ tert-butyl EAT78 aa or ab—F —CF₃ —H EAT79 aa or ab —F —CF₃ —Cl EAT80 aa or ab —F —CF₃ —Br EAT81aa or ab —F —CF₃ —F EAT82 aa or ab —F —CF₃ —CH₃ EAT83 aa or ab —F —CF₃—OCH₃ EAT84 aa or ab —F —CF₃ —OCH₂CH₃ EAT85 aa or ab —F —CF₃ —CF₃ EAT86aa or ab —F —CF₃ —OCF₃ EAT87 aa or ab —F —CF₃ iso-propyl EAT88 aa or ab—F —CF₃ tert-butyl EAT89 aa or ab —F —OCF₃ —H EAT90 aa or ab —F —OCF₃—Cl EAT91 aa or ab —F —OCF₃ —Br EAT92 aa or ab —F —OCF₃ —F EAT93 aa orab —F —OCF₃ —CH₃ EAT94 aa or ab —F —OCF₃ —OCH₃ EAT95 aa or ab —F —OCF₃—OCH₂CH₃ EAT96 aa or ab —F —OCF₃ —CF₃ EAT97 aa or ab —F —OCF₃ —OCF₃EAT98 aa or ab —F —OCF₃ iso-propyl EAT99 aa or ab —F —OCF₃ tert-butylEAT100 aa or ab —F iso-propyl —H EAT101 aa or ab —F iso-propyl —ClEAT102 aa or ab —F iso-propyl —Br EAT103 aa or ab —F iso-propyl —FEAT104 aa or ab —F iso-propyl —CH₃ EAT105 aa or ab —F iso-propyl —OCH₃EAT106 aa or ab —F iso-propyl —OCH₂CH₃ EAT107 aa or ab —F iso-propyl—CF₃ EAT108 aa or ab —F iso-propyl —OCF₃ EAT109 aa or ab —F iso-propyliso-propyl EAT110 aa or ab —F iso-propyl tert-butyl EAT111 aa or ab —Ftert-butyl —H EAT112 aa or ab —F tert-butyl —Cl EAT113 aa or ab —Ftert-butyl —Br EAT114 aa or ab —F tert-butyl —F EAT115 aa or ab —Ftert-butyl —CH₃ EAT116 aa or ab —F tert-butyl —OCH₃ EAT117 aa or ab —Ftert-butyl —OCH₂CH₃ EAT118 aa or ab —F tert-butyl —CF₃ EAT119 aa or ab—F tert-butyl —OCF₃ EAT120 aa or ab —F tert-butyl iso-propyl EAT121 aaor ab —F tert-butyl tert-butyl EAU1 aa or ab —CF₃ —H —H EAU2 aa or ab—CF₃ —H —Cl EAU3 aa or ab —CF₃ —H —Br EAU4 aa or ab —CF₃ —H —F EAU5 aaor ab —CF₃ —H —CH₃ EAU6 aa or ab —CF₃ —H —OCH₃ EAU7 aa or ab —CF₃ —H—OCH₂CH₃ EAU8 aa or ab —CF₃ —H —CF₃ EAU9 aa or ab —CF₃ —H —OCF₃ EAU10 aaor ab —CF₃ —H iso-propyl EAU11 aa or ab —CF₃ —H tert-butyl EAU12 aa orab —CF₃ —Cl —H EAU13 aa or ab —CF₃ —Cl —Cl EAU14 aa or ab —CF₃ —Cl —BrEAU15 aa or ab —CF₃ —Cl —F EAU16 aa or ab —CF₃ —Cl —CH₃ EAU17 aa or ab—CF₃ —Cl —OCH₃ EAU18 aa or ab —CF₃ —Cl —OCH₂CH₃ EAU19 aa or ab —CF₃ —Cl—CF₃ EAU20 aa or ab —CF₃ —Cl —OCF₃ EAU21 aa or ab —CF₃ —Cl iso-propylEAU22 aa or ab —CF₃ —Cl tert-butyl EAU23 aa or ab —CF₃ —Br —H EAU24 aaor ab —CF₃ —Br —Cl EAU25 aa or ab —CF₃ —Br —Br EAU26 aa or ab —CF₃ —Br—F EAU27 aa or ab —CF₃ —Br —CH₃ EAU28 aa or ab —CF₃ —Br —OCH₃ EAU29 aaor ab —CF₃ —Br —OCH₂CH₃ EAU30 aa or ab —CF₃ —Br —CF₃ EAU31 aa or ab —CF₃—Br —OCF₃ EAU32 aa or ab —CF₃ —Br iso-propyl EAU33 aa or ab —CF₃ —Brtert-butyl EAU34 aa or ab —CF₃ —F —H EAU35 aa or ab —CF₃ —F —Cl EAU36 aaor ab —CF₃ —F —Br EAU37 aa or ab —CF₃ —F —F EAU38 aa or ab —CF₃ —F —CH₃EAU39 aa or ab —CF₃ —F —OCH₃ EAU40 aa or ab —CF₃ —F —OCH₂CH₃ EAU41 aa orab —CF₃ —F —CF₃ EAU42 aa or ab —CF₃ —F —OCF₃ EAU43 aa or ab —CF₃ —Fiso-propyl EAU44 aa or ab —CF₃ —F tert-butyl EAU45 aa or ab —CF₃ —CH₃ —HEAU46 aa or ab —CF₃ —CH₃ —Cl EAU47 aa or ab —CF₃ —CH₃ —Br EAU48 aa or ab—CF₃ —CH₃ —F EAU49 aa or ab —CF₃ —CH₃ —CH₃ EAU50 aa or ab —CF₃ —CH₃—OCH₃ EAU51 aa or ab —CF₃ —CH₃ —OCH₂CH₃ EAU52 aa or ab —CF₃ —CH₃ —CF₃EAU53 aa or ab —CF₃ —CH₃ —OCF₃ EAU54 aa or ab —CF₃ —CH₃ iso-propyl EAU55aa or ab —CF₃ —CH₃ tert-butyl EAU56 aa or ab —CF₃ —OCH₃ —H EAU57 aa orab —CF₃ —OCH₃ —Cl EAU58 aa or ab —CF₃ —OCH₃ —Br EAU59 aa or ab —CF₃—OCH₃ —F EAU60 aa or ab —CF₃ —OCH₃ —CH₃ EAU61 aa or ab —CF₃ —OCH₃ —OCH₃EAU62 aa or ab —CF₃ —OCH₃ —OCH₂CH₃ EAU63 aa or ab —CF₃ —OCH₃ —CF₃ EAU64aa or ab —CF₃ —OCH₃ —OCF₃ EAU65 aa or ab —CF₃ —OCH₃ iso-propyl EAU66 aaor ab —CF₃ —OCH₃ tert-butyl EAU67 aa or ab —CF₃ —OCH₂CH₃ —H EAU68 aa orab —CF₃ —OCH₂CH₃ —Cl EAU69 aa or ab —CF₃ —OCH₂CH₃ —Br EAU70 aa or ab—CF₃ —OCH₂CH₃ —F EAU71 aa or ab —CF₃ —OCH₂CH₃ —CH₃ EAU72 aa or ab —CF₃—OCH₂CH₃ —OCH₃ EAU73 aa or ab —CF₃ —OCH₂CH₃ —OCH₂CH₃ EAU74 aa or ab —CF₃—OCH₂CH₃ —CF₃ EAU75 aa or ab —CF₃ —OCH₂CH₃ —OCF₃ EAU76 aa or ab —CF₃—OCH₂CH₃ iso-propyl EAU77 aa or ab —CF₃ —OCH₂CH₃ tert-butyl EAU78 aa orab —CF₃ —CF₃ —H EAU79 aa or ab —CF₃ —CF₃ —Cl EAU80 aa or ab —CF₃ —CF₃—Br EAU81 aa or ab —CF₃ —CF₃ —F EAU82 aa or ab —CF₃ —CF₃ —CH₃ EAU83 aaor ab —CF₃ —CF₃ —OCH₃ EAU84 aa or ab —CF₃ —CF₃ —OCH₂CH₃ EAU85 aa or ab—CF₃ —CF₃ —CF₃ EAU86 aa or ab —CF₃ —CF₃ —OCF₃ EAU87 aa or ab —CF₃ —CF₃iso-propyl EAU88 aa or ab —CF₃ —CF₃ tert-butyl EAU89 aa or ab —CF₃ —OCF₃—H EAU90 aa or ab —CF₃ —OCF₃ —Cl EAU91 aa or ab —CF₃ —OCF₃ —Br EAU92 aaor ab —CF₃ —OCF₃ —F EAU93 aa or ab —CF₃ —OCF₃ —CH₃ EAU94 aa or ab —CF₃—OCF₃ —OCH₃ EAU95 aa or ab —CF₃ —OCF₃ —OCH₂CH₃ EAU96 aa or ab —CF₃ —OCF₃—CF₃ EAU97 aa or ab —CF₃ —OCF₃ —OCF₃ EAU98 aa or ab —CF₃ —OCF₃iso-propyl EAU99 aa or ab —CF₃ —OCF₃ tert-butyl EAU100 aa or ab —CF₃iso-propyl —H EAU101 aa or ab —CF₃ iso-propyl —Cl EAU102 aa or ab —CF₃iso-propyl —Br EAU103 aa or ab —CF₃ iso-propyl —F EAU104 aa or ab —CF₃iso-propyl —CH₃ EAU105 aa or ab —CF₃ iso-propyl —OCH₃ EAU106 aa or ab—CF₃ iso-propyl —OCH₂CH₃ EAU107 aa or ab —CF₃ iso-propyl —CF₃ EAU108 aaor ab —CF₃ iso-propyl —OCF₃ EAU109 aa or ab —CF₃ iso-propyl iso-propylEAU110 aa or ab —CF₃ iso-propyl tert-butyl EAU111 aa or ab —CF₃tert-butyl —H EAU112 aa or ab —CF₃ tert-butyl —Cl EAU113 aa or ab —CF₃tert-butyl —Br EAU114 aa or ab —CF₃ tert-butyl —F EAU115 aa or ab —CF₃tert-butyl —CH₃ EAU116 aa or ab —CF₃ tert-butyl —OCH₃ EAU117 aa or ab—CF₃ tert-butyl —OCH₂CH₃ EAU118 aa or ab —CF₃ tert-butyl —CF₃ EAU119 aaor ab —CF₃ tert-butyl —OCF₃ EAU120 aa or ab —CF₃ tert-butyl iso-propylEAU121 aa or ab —CF₃ tert-butyl tert-butyl EAV1 aa or ab —CH₃ —H —H EAV2aa or ab —CH₃ —H —Cl EAV3 aa or ab —CH₃ —H —Br EAV4 aa or ab —CH₃ —H —FEAV5 aa or ab —CH₃ —H —CH₃ EAV6 aa or ab —CH₃ —H —OCH₃ EAV7 aa or ab—CH₃ —H —OCH₂CH₃ EAV8 aa or ab —CH₃ —H —CF₃ EAV9 aa or ab —CH₃ —H —OCF₃EAV10 aa or ab —CH₃ —H iso-propyl EAV11 aa or ab —CH₃ —H tert-butylEAV12 aa or ab —CH₃ —Cl —H EAV13 aa or ab —CH₃ —Cl —Cl EAV14 aa or ab—CH₃ —Cl —Br EAV15 aa or ab —CH₃ —Cl —F EAV16 aa or ab —CH₃ —Cl —CH₃EAV17 aa or ab —CH₃ —Cl —OCH₃ EAV18 aa or ab —CH₃ —Cl —OCH₂CH₃ EAV19 aaor ab —CH₃ —Cl —CF₃ EAV20 aa or ab —CH₃ —Cl —OCF₃ EAV21 aa or ab —CH₃—Cl iso-propyl EAV22 aa or ab —CH₃ —Cl tert-butyl EAV23 aa or ab —CH₃—Br —H EAV24 aa or ab —CH₃ —Br —Cl EAV25 aa or ab —CH₃ —Br —Br EAV26 aaor ab —CH₃ —Br —F EAV27 aa or ab —CH₃ —Br —CH₃ EAV28 aa or ab —CH₃ —Br—OCH₃ EAV29 aa or ab —CH₃ —Br —OCH₂CH₃ EAV30 aa or ab —CH₃ —Br —CF₃EAV31 aa or ab —CH₃ —Br —OCF₃ EAV32 aa or ab —CH₃ —Br iso-propyl EAV33aa or ab —CH₃ —Br tert-butyl EAV34 aa or ab —CH₃ —F —H EAV35 aa or ab—CH₃ —F —Cl EAV36 aa or ab —CH₃ —F —Br EAV37 aa or ab —CH₃ —F —F EAV38aa or ab —CH₃ —F —CH₃ EAV39 aa or ab —CH₃ —F —OCH₃ EAV40 aa or ab —CH₃—F —OCH₂CH₃ EAV41 aa or ab —CH₃ —F —CF₃ EAV42 aa or ab —CH₃ —F —OCF₃EAV43 aa or ab —CH₃ —F iso-propyl EAV44 aa or ab —CH₃ —F tert-butylEAV45 aa or ab —CH₃ —CH₃ —H EAV46 aa or ab —CH₃ —CH₃ —Cl EAV47 aa or ab—CH₃ —CH₃ —Br EAV48 aa or ab —CH₃ —CH₃ —F EAV49 aa or ab —CH₃ —CH₃ —CH₃EAV50 aa or ab —CH₃ —CH₃ —OCH₃ EAV51 aa or ab —CH₃ —CH₃ —OCH₂CH₃ EAV52aa or ab —CH₃ —CH₃ —CF₃ EAV53 aa or ab —CH₃ —CH₃ —OCF₃ EAV54 aa or ab—CH₃ —CH₃ iso-propyl EAV55 aa or ab —CH₃ —CH₃ tert-butyl EAV56 aa or ab—CH₃ —OCH₃ —H EAV57 aa or ab —CH₃ —OCH₃ —Cl EAV58 aa or ab —CH₃ —OCH₃—Br EAV59 aa or ab —CH₃ —OCH₃ —F EAV60 aa or ab —CH₃ —OCH₃ —CH₃ EAV61 aaor ab —CH₃ —OCH₃ —OCH₃ EAV62 aa or ab —CH₃ —OCH₃ —OCH₂CH₃ EAV63 aa or ab—CH₃ —OCH₃ —CF₃ EAV64 aa or ab —CH₃ —OCH₃ —OCF₃ EAV65 aa or ab —CH₃—OCH₃ iso-propyl EAV66 aa or ab —CH₃ —OCH₃ tert-butyl EAV67 aa or ab—CH₃ —OCH₂CH₃ —H EAV68 aa or ab —CH₃ —OCH₂CH₃ —Cl EAV69 aa or ab —CH₃—OCH₂CH₃ —Br EAV70 aa or ab —CH₃ —OCH₂CH₃ —F EAV71 aa or ab —CH₃—OCH₂CH₃ —CH₃ EAV72 aa or ab —CH₃ —OCH₂CH₃ —OCH₃ EAV73 aa or ab —CH₃—OCH₂CH₃ —OCH₂CH₃ EAV74 aa or ab —CH₃ —OCH₂CH₃ —CF₃ EAV75 aa or ab —CH₃—OCH₂CH₃ —OCF₃ EAV76 aa or ab —CH₃ —OCH₂CH₃ iso-propyl EAV77 aa or ab—CH₃ —OCH₂CH₃ tert-butyl EAV78 aa or ab —CH₃ —CF₃ —H EAV79 aa or ab —CH₃—CF₃ —Cl EAV80 aa or ab —CH₃ —CF₃ —Br EAV81 aa or ab —CH₃ —CF₃ —F EAV82aa or ab —CH₃ —CF₃ —CH₃ EAV83 aa or ab —CH₃ —CF₃ —OCH₃ EAV84 aa or ab—CH₃ —CF₃ —OCH₂CH₃ EAV85 aa or ab —CH₃ —CF₃ —CF₃ EAV86 aa or ab —CH₃—CF₃ —OCF₃ EAV87 aa or ab —CH₃ —CF₃ iso-propyl EAV88 aa or ab —CH₃ —CF₃tert-butyl EAV89 aa or ab —CH₃ —OCF₃ —H EAV90 aa or ab —CH₃ —OCF₃ —ClEAV91 aa or ab —CH₃ —OCF₃ —Br EAV92 aa or ab —CH₃ —OCF₃ —F EAV93 aa orab —CH₃ —OCF₃ —CH₃ EAV94 aa or ab —CH₃ —OCF₃ —OCH₃ EAV95 aa or ab —CH₃—OCF₃ —OCH₂CH₃ EAV96 aa or ab —CH₃ —OCF₃ —CF₃ EAV97 aa or ab —CH₃ —OCF₃—OCF₃ EAV98 aa or ab —CH₃ —OCF₃ iso-propyl EAV99 aa or ab —CH₃ —OCF₃tert-butyl EAV100 aa or ab —CH₃ iso-propyl —H EAV101 aa or ab —CH₃iso-propyl —Cl EAV102 aa or ab —CH₃ iso-propyl —Br EAV103 aa or ab —CH₃iso-propyl —F EAV104 aa or ab —CH₃ iso-propyl —CH₃ EAV105 aa or ab —CH₃iso-propyl —OCH₃ EAV106 aa or ab —CH₃ iso-propyl —OCH₂CH₃ EAV107 aa orab —CH₃ iso-propyl —CF₃ EAV108 aa or ab —CH₃ iso-propyl —OCF₃ EAV109 aaor ab —CH₃ iso-propyl iso-propyl EAV110 aa or ab —CH₃ iso-propyltert-butyl EAV111 aa or ab —CH₃ tert-butyl —H EAV112 aa or ab —CH₃tert-butyl —Cl EAV113 aa or ab —CH₃ tert-butyl —Br EAV114 aa or ab —CH₃tert-butyl —F EAV115 aa or ab —CH₃ tert-butyl —CH₃ EAV116 aa or ab —CH₃tert-butyl —OCH₃ EAV117 aa or ab —CH₃ tert-butyl —OCH₂CH₃ EAV118 aa orab —CH₃ tert-butyl —CF₃ EAV119 aa or ab —CH₃ tert-butyl —OCF₃ EAV120 aaor ab —CH₃ tert-butyl iso-propyl EAV121 aa or ab —CH₃ tert-butyltert-butyl

TABLE 28 (IIIbb)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₉ EBB —Cl —Cl EBC —Cl —F EBD —Cl —CH₃ EBE —F —Cl EBF —F —F EBG —F —CH₃EBH —CF₃ —Cl EBI —CF₃ —F EBJ —CF₃ —CH₃

TABLE 29 (IIIcc)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₉ EBK —Cl —Cl EBL —Cl —F EBM —Cl —CH₃ EBN —F —Cl EBO —F —F EBP —F —CH₃EBQ —CF₃ —Cl EBR —CF₃ —F EBS —CF₃ —CH₃

TABLE 30 (IIIdd)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₉ EBT —Cl —Cl EBU —Cl —F EBV —Cl —CH₃ EBW —F —Cl EBX —F —F EBY —F —CH₃EBZ —CF₃ —Cl ECA —CF₃ —F ECB —CF₃ —CH₃

TABLE 31 (IIIee)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FAA —Cl —Cl FAB —Cl —F FAC —Cl —Br FAD —Cl —OCH₃ FAE —Cl—OCH₂CH₃ FAF —F —Cl FAG —F —F FAH —F —Br FAI —F —OCH₃ FAJ —F —OCH₂CH₃FAK —CF₃ —Cl FAL —CF₃ —F FAM —CF₃ —Br FAN —CF₃ —OCH₃ FAO —CF₃ —OCH₂CH₃

TABLE 32 (IIIff)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FAP —Cl —Cl FAQ —Cl —F FAR —Cl —Br FAS —Cl —OCH₃ FAT —Cl—OCH₂CH₃ FAU —F —Cl FAV —F —F FAW —F —Br FAX —F —OCH₃ FAY —F —OCH₂CH₃FAZ —CF₃ —Cl FBA —CF₃ —F FBB —CF₃ —Br FBC —CF₃ —OCH₃ FBD —CF₃ —OCH₂CH₃

TABLE 33 (IIIgg)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FBE —Cl —Cl FBF —Cl —F FBG —Cl —Br FBH —Cl —OCH₃ FBI —Cl—OCH₂CH₃ FBJ —F —Cl FBK —F —F FBL —F —Br FBM —F —OCH₃ FBN —F —OCH₂CH₃FBO —CF₃ —Cl FBP —CF₃ —F FBQ —CF₃ —Br FBR —CF₃ —OCH₃ FBS —CF₃ —OCH₂CH₃

TABLE 34 (IIIhh)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FBT —Cl —Cl FBU —Cl —F FBV —Cl —Br FBW —Cl —OCH₃ FBX —Cl—OCH₂CH₃ FBY —F —Cl FBZ —F —F FCA —F —Br FCB —F —OCH₃ FCC —F —OCH₂CH₃FCD —CF₃ —Cl FCE —CF₃ —F FCF —CF₃ —Br FCG —CF₃ —OCH₃ FCH —CF₃ —OCH₂CH₃

TABLE 35 (IIIii)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FCI —Cl —Cl FCJ —Cl —F FCK —Cl —Br FCL —Cl —OCH₃ FCM —Cl—OCH₂CH₃ FCN —F —Cl FCO —F —F FCP —F —Br FCQ —F —OCH₃ FCR —F —OCH₂CH₃FCS —CF₃ —Cl FCT —CF₃ —F FCU —CF₃ —Br FCV —CF₃ —OCH₃ FCW —CF₃ —OCH₂CH₃

TABLE 36 (IIIjj)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R_(14′) FCX —Cl —Cl FCY —Cl —F FCZ —Cl —Br FDA —Cl —OCH₃ FDB —Cl—OCH₂CH₃ FDC —F —Cl FDD —F —F FDE —F —Br FDF —F —OCH₃ FDG —F —OCH₂CH₃FDH —CF₃ —Cl FDI —CF₃ —F FDJ —CF₃ —Br FDK —CF₃ —OCH₃ FDL —CF₃ —OCH₂CH₃

5.5 Definitions

As used herein, the terms used above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.Representative branched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl,3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₆)haloalkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms as defined above for—(C₁-C₆)alkyl that is substituted with 1, 2 or 3 independently selectedhalo groups.

“—(C₁-C₆)hydroxyalkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms as defined above for—(C₁-C₆)alkyl that is substituted with 1, 2 or 3 hydroxyl groups.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl and the like.

“—(C₂-C₆)haloalkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond as defined above for —(C₂-C₆)alkenyl that issubstituted with 1, 2 or 3 independently selected halo groups.

“—(C₂-C₆)hydroxyalkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond as defined above for —(C₂-C₆)alkenyl that issubstituted with 1, 2 or 3 hydroxyl groups.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

“—(C₂-C₆)haloalkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond that is substituted with 1, 2 or 3independently selected halo groups.

“—(C₂-C₆)hydroxyalkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond that is substituted with 1, 2 or 3 hydroxylgroups.

“—(C₁-C₆)alkoxy” means a straight chain or branched non cyclichydrocarbon having one or more ether groups and from 1 to 6 carbonatoms. Representative straight chain and branched —(C₁-C₆)alkoxysinclude methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy,methoxymethyl, 2-methoxyethyl, 5-methoxypentyl, 3-ethoxybutyl, and thelike.

“—(C₁-C₆)alkoxy(C₂-C₆)alkyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkoxy group that issubstituted with a —(C₂-C₆)alkyl group.

“—(C₁-C₆)alkoxy(C₂-C₆)alkenyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkoxy group that issubstituted with a —(C₂-C₆)alkenyl group.

“—(C₁-C₆)alkoxy(C₂-C₆)alkynyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms that is substituted with a —(C₂-C₆)alkynyl group.

“—(C₁-C₆)alkoxy(C₃-C₈)cycloalkyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkyl group that issubstituted with a —(C₃-C₈)cycloalkyl group

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl, and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative —(C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative —(C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, a 5-membered heterocycle can contain up to4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatoms,and a 7-membered heterocycle can contain up to 5 heteroatoms. Eachheteroatom is independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(3- to 7-membered)heterocycle can be attached via a nitrogen or carbonatom. Representative -(3- to 7-membered)heterocycles include pyridyl,furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl,thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl,dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur, orat least two carbon atoms of one or both of the rings are replaced witha heteroatom independently selected from nitrogen, oxygen, and sulfur.In one embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members where at least one carbon atom is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- or 6-membered)heteroaryl's ring containsat least one carbon atom. Representative -(5- or 6-membered)heteroarylsinclude pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, CHBrCl, CHClI, and—CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —CI₃.

“-Halogen” or “-Halo” means —F, —Cl, —Br, or —I.

“(C₂-C₆)bridge” as used herein means a hydrocarbon chain containing 2 to6 carbon atoms joining two atoms of the piperidine,1,2,3,6-tetrahydropyridine or piperazine ring of the compounds offormula I, IA, II and/or III to form a fused bicyclic ring system. Thepositions of the piperidine, 1,2,3,6-tetrahydropyridine or piperazinering are denoted as follows:

For example, compounds of the invention can comprise a (C₂-C₆)bridgejoining positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridineor piperazine ring (two R₃ groups can together form a (C₂-C₆)bridge).Examples of compounds where two R₃ groups can together form a(C₂-C₆)bridge include compounds comprising the following ring systems:8-aza-bicyclo[3.2.1]octane; 8-azabicyclo[3.2.1]oct-3-ene;3,8-diazabicyclo[3.2.1]octane; 8-azabicyclo[3.2.1]oct-6-ene;8-azabicyclo[3.2.1]octa-3,6-diene; 3,8-diazabicyclo[3.2.1]oct-6-ene;9-aza-bicyclo[3.3.1]nonane; 9-azabicyclo[3.3.1]non-3-ene;9-azabicyclo[3.3.1]non-6-ene; 9-azabicyclo[3.3.1]nona-3,6-diene;9-azabicyclo[3.3.1]nona-3,7-diene; 3,9-diazabicyclo[3.3.1]nonane;3,9-diazabicyclo[3.3.1]non-6-ene; 3,9-diazabicyclo[3.3.1]non-7-ene;10-aza-bicyclo[4.3.1]decane; 10-azabicyclo[4.3.1]dec-8-ene;8,10-diazabicyclo[4.3.1]decane; 8,10-diazabicyclo[4.3.1]dec-3-ene;8,10-diazabicyclo[4.3.1]dec-4-ene; 8-azabicyclo[4.3.1]dec-4-ene;8-azabicyclo[4.3.1]dec-3-ene; 8-azabicyclo[4.3.1]deca-2,6(10)-diene;8-azabicyclo[4.3.1]deca-3,6(10)-diene;8-azabicyclo[4.3.1]deca-4,6(10)-diene; 11-aza-bicyclo[5.3.1]undecane;11-azabicyclo[5.3.1]undec-8-ene; 9,11-diazabicyclo[5.3.1]undecane;12-aza-bicyclo[6.3.1]dodecane; 12-azabicyclo[6.3.1]dodec-9-ene; and10,12-diazabicyclo[6.3.1]dodecane.

In connection with the Ar₂ group

when E is —NH(C₁-C₆)alkyl it is to be understood that the dashed line inthe above Ar₂ group is absent, i.e., the Ar₂ group is

where Y₁, Y₂, Y₃, R₁₄, c and t are as defined above for compounds offormula I. When E is ═O, ═S, ═C(C₁-C₅)alkyl, ═C(C₁-C₅)alkenyl, or═N—OR₂₀, it is to be understood that the dashed line in the above Ar₂group is present, i.e., the Ar₂ group is

respectively, where Y₁, Y₂, Y₃, R₁₄, R₂₀, c and t are as defined abovefor compounds of formula I.

The phrase “pyridyl group” means

where R₁, R₂, and n are as defined above for compounds of formula I, andwhere the numbers designate the position of each atom in the ring.

The phrase “pyrazinyl group” means

where R₁, R₂, and p are as defined above for compounds of formula I.

The phrase “pyrimidinyl group” means

where R₁, R₂, and p are as defined above for compounds of formula I.

The phrase “pyridazinyl group” means

where R₁, R₂, and p are as defined above for compounds of formula I.

The phrase “benzoimidiazolyl group” means

where R₈, R₉, and R₂₀ are as defined above for compounds of formula I.

The phrase “benzothiazolyl group” means

where R₈ and R₉ are as defined above for compounds of formula I.

The phrase “benzooxazolyl group” means

where R₈ and R₉ are as defined above for compounds of formula I.

The phrase phenyl group means

where R₁₄ and s are as defined for compounds of formula I.

The phrase “tetrahydropiperidyl ring” means

where the numbers designate the position of each atom of thetetrahydropiperidyl ring.

The term “animal,” includes, but is not limited to, a cow, monkey,baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig, and human.

The phrase “pharmaceutically acceptable derivative,” as used herein,includes any pharmaceutically acceptable salt, solvate, radiolabeled,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of a compoundof formula I of the invention. In one embodiment, the pharmaceuticallyacceptable derivative is a pharmaceutically acceptable salt, solvate,radiolabeled, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a compound of formula I of the invention. In anotherembodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, e.g., of a compound of formula I ofthe invention.

The phrase “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from a compound offormula I including a salt formed from an acid and a basic functionalgroup, such as a nitrogen group, of a compound of formula I.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a compound of formula I having an acidic functional group,such as a carboxylic acid functional group, and a pharmaceuticallyacceptable inorganic or organic base. Suitable bases include, but arenot limited to, hydroxides of alkali metals such as sodium, potassium,cesium, and lithium; hydroxides of alkaline earth metal such as calciumand magnesium; hydroxides of other metals, such as aluminum and zinc;ammonia and organic amines, such as unsubstituted or hydroxy-substitutedmono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine;pyridine; picoline; N-methyl,N-ethylamine; diethylamine; triethylamine;mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines), such as mono-,bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. One skilled in the art will recognize that, e.g., acid additionsalts of a compound of formula I can be prepared by reaction of thecompounds with the appropriate acid via a variety of known methods.

Compounds of formula I encompass all solvates of compounds of formula I.“Solvates” are known in the art and are considered to be a combination,physical association and/or solvation of a compound of formula I with asolvent molecule, e.g., a disolvate, monosolvate or hemisolvate when theratio of the solvent molecule to the molecule of the compound of formulaI is 2:1, 1:1 or 1:2, respectively. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances, the solvate can be isolated, for examplewhen one or more solvent molecules are incorporated into the crystallattice of a crystalline solid. Thus, “solvate,” as used herein,encompasses both solution-phase and isolatable solvates. A compound offormula I of the invention may be present as a solvated form with apharmaceutically acceptable solvent, such as water, methanol, ethanol,and the like, and it is intended that the invention include bothsolvated and unsolvated compound of formula I forms. As “hydrate”relates to a particular subgroup of solvates, i.e., where the solventmolecule is water, hydrates are included within the solvates of theinvention. Preparation of solvates is known in the art. For example, M.Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004), describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparations of solvates, hemisolvate, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1), article 12 (2004), and A. L. Bingham et al., Chem. Commun.,603-604 (2001). A typical, non-limiting, process involves dissolving thecompound of formula I in a desired amount of the desired solvent(organic, water or mixtures thereof) at temperatures above about 20° C.to about 25° C., cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques, for example, infrared spectroscopy, can be usedto show the presence of the solvent in a crystal of the solvate.

The invention disclosed herein is also meant to encompass all prodrugsof the compounds of the invention. “Prodrugs” are known in the art and,while not necessarily possessing any pharmaceutical activity as such,are considered to be any covalently bonded carrier(s) that releases theactive parent drug in vivo. In general, such prodrugs will be afunctional derivative of a compound of formula I which is readilyconvertible in vivo, e.g., by being metabolized, into the requiredcompound of formula I. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described in, forexample, Design of prodrugs, H. Bundgaard ed., Elsevier (1985); “Drugand Enzyme Targeting, Part A,” K. Widder et al eds., Vol. 112 in Methodsin Enzymology, Academic Press (1985); Bundgaard, “Design and Applicationof Prodrugs,” Chapter 5 (pp. 113-191) in A Textbook of Drug Design andDevelopment, P. Krogsgaard-Larsen and H. Bundgaard eds., HarwoodAcademic Publishers (1991); Bundgaard et al., Adv. Drug Delivery Revs.8:1-38 (1992); Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); andKakeya et al., Chem. Pharm. Bull. 32:692 (1984).

In addition, one or more hydrogen, carbon or other atoms of a compoundof formula I can be replaced by an isotope of the hydrogen, carbon orother atoms. Compounds of formula I include all radiolabeled forms ofcompounds of formula I. Such a “radiolabeled,” “radiolabeled form”, andthe like of a compound of formula I, each of which is encompassed by theinvention, is useful as a research and/or diagnostic tool in metabolismpharmacokinetic studies and in binding assays. Examples of isotopes thatcan be incorporated into a compound of formula I of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Radiolabeled compounds of theinvention can be prepared by methods known in the art. For example,tritiated compounds of formula I can be prepared by introducing tritiuminto the particular compound of Formula I, for example, by catalyticdehalogenation with tritium. This method may include reacting a suitablyhalogen-substituted precursor of a compound of Formula I with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

A compound of formula I can contain one or more asymmetric centers andmay thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Compounds of formula I encompass all such possibleforms as well as their racemic and resolved forms or any mixturethereof. When a compound of formula I contains an olefinic double bondor other center of geometric asymmetry, and unless specified otherwise,it is intended to include all “geometric isomers,” e.g., both E and Zgeometric isomers. All “tautomers,” e.g., ketone-enol, amide-imidicacid, lactam-lactim, enamine-imine, amine-imine, and enamine-eniminetautomers, are intended to be encompassed by the invention as well.

As used herein, the terms “stereoisomer,” “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Optical isomers of a compound of formula I can be obtained by knowntechniques such as chiral chromatography or formation of diastereomericsalts from an optically active acid or base.

Optical purity can be stated in terms of enantiomeric excess (% ee),which is determined by the formula:

${\% \mspace{14mu} {ee}} = {\left\lbrack \frac{{{major}\mspace{14mu} {{enantiomer}({mol})}} - {{minor}\mspace{14mu} {{enentiomer}({mol})}}}{{{major}\mspace{14mu} {{enantiomer}({mol})}} + {{minor}\mspace{14mu} {{enentiomer}({mol})}}} \right\rbrack \times 100{\%.}}$

The phrase “effective amount,” when used in connection with a compoundof formula I means an amount effective for: (a) treating or preventing aCondition; or (b) inhibiting TRPV1 function in a cell.

The phrase “effective amount,” when used in connection with the anothertherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

The phrase “therapeutic index,” describes the gap between the dose thatis effective, and the dose that induces adverse effects.

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, the number of second groups is one or two. In anotherembodiment, the number of second groups is one.

The term “MeOH” means methanol, i.e., methyl alcohol.

The term “EtOH” means ethanol, i.e., ethyl alcohol.

The term “t-BuOH” means tert-butyl alcohol, i.e., 2-methylpropan-2-ol.

The term “THF” means tetrahydrofuran.

The term “DMF” means N,N-dimethylformamide.

The term “DCM” means methylene chloride, i.e., dichloromethane.

The term “DCE” means dichloroethane.

The term “DME” means 1,2-dimethoxyethane, i.e., ethylene glycol dimethylether.

The term “EtOAc” means ethyl acetate.

The term “NH₄OH” means ammonium hydroxide.

The term “TEA” means triethylamine.

The term “MeCN” means acetonitrile.

The term “NaH” means sodium hydride.

The term “AcOH” means acetic acid.

The term “DIEA” means N,N-diisopropylethylamine orN-ethyldiisopropylamine, i.e., N-ethyl-N-isopropylpropan-2-amine.

The term “DMSO” means dimethylsulfoxide, i.e., methylsulfinylmethane.

The term “DAST” means (diethylamino) sulfur trifluoride.

The term “LiHMDS” means lithium hexamethyldisilazide.

The term “BuLi” means butyl lithium.

The term “DPPP” means 1,3-bis(diphenylphosphino)propane.

The term “BOC” means tert-butyloxycarbonyl:

The term “TBS” means tert-butyldimethylsilyl:

The term “TsOH” means p-toluenesulfonic acid or toluene-4-sulfonic acid.

The term “TMSBr” means trimethylsilyl bromide or (CH₃)₃SiBr.

The term “TMSCl” means trimethylsilyl chloride or (CH₃)₃SiCl.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrases “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasingthe overall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof.

5.6 Methods for Making Compounds of Formula I

The compounds of formula I can be made using conventional organicsynthesis or by the illustrative methods shown in the schemes below.

5.6.1 Methods for Making Compounds of Formula I Where W is C and theDashed Line is Absent

The compounds of formula I where W is C and the dashed line is absent,i.e., “Piperidine Compounds,” can be made using conventional organicsynthesis or by the illustrative methods shown in the schemes below.

5.6.1.1 Methods for Making the Piperidine Compounds Here X is O and R₄is —Oh or —F

The compounds of formula I where X is O and R₄ is —OH can be obtained bythe illustrative method shown below in scheme 1.1:

where Ar₂, R₁, R₂, R₃, n, m, and p are as defined for compounds offormula I and L is a halogen.

To a solution of 2a-d in the presence of tert-butyl lithium (1.7M inheptane, 6.45 mL, 11.12 mmol) in THF (20 mL) at −78° C. is addeddropwise compound 1 in anhydrous THF (10 mL). The reaction mixture isstirred at −78° C. for about 3 h and is quenched with aqueous NH₄Cl atabout 0° C., and then the organic and aqueous layers are separated. Theaqueous layer is extracted with THF, the organic portions are combined,and dried (Na₂SO₄). The resulting solution is concentrated under reducedpressure to provide a residue. The residue is chromatographed usingsilica gel column chromatography that is eluted with ethylacetate/hexane (gradient elution from 30:70 to 70:30) to provide aPiperidine Compound where X is O and R₄ is —OH (3a-d).

The compounds of formula 2a-d are commercially available or can beprepared by methods known in the art.

Compound 1 can be obtained by reacting 4 with an isocyanate as shownbelow in scheme 1.2:

where R₃, and m are as defined above and R is Ar₂.

Compound 4 (20 mmol) in chloroform is added to a solution of anisocyanate of formula R—NCO in chloroform (30 mL) at about 25° C. Theresultant reaction mixture is stirred for about 3 h at about 25° C. thenconcentrated under reduced pressure to provide a residue. The residue issuspended in THF (50 mL) and 4N HCl (50 mL) is added to the resultingsolution. The reaction mixture allowed to stir for about 12 h. Thereaction mixture is then poured into water (200 mL), and the pH isadjusted to 10 or greater with aqueous potassium carbonate base. Theresulting solution is extracted with ethyl acetate and the ethyl acetatelayers are combined, dried (MgSO₄) and concentrated under reducedpressure to provide a residue that can be chromatographed using flashchromatography on a silica gel column eluted with ethyl acetate/hexane(gradient elution from 30:70 to 70:30) to provide compound 1.

Isocyanates of formula Ar₂-NCO are commercially available or are can beprepared by reacting an amine Ar₂NH₂ with phosgene according to knownmethods (See, e.g., H. Eckert and B. Foster, Angew. Chem. Int. Ed.Engl., 26, 894 (1987); H. Eckert, Ger. Offen. DE 3 440 141; Chem. Abstr.106, 4294d (1987); and L. Contarca et al., Synthesis, 553-576 (1996).For example, an amine Ar₂NH₂ can be reacted with triphosgene as shownbelow.

Typically a solution of triphosgene (about 0.3 equivalents or 0.3 eq.)in DCM (about 0.3M) is slowly added to a stirred solution of the amine(about 1.0 eq.) in DCM (about 0.3M) at about 25° C. The reaction mixtureis then stirred at about 25° C. for about 10 min. and the temperature israised to about 70° C. After stirring at 70° C. for 3 h., the reactionmixture is cooled to 25° C., filtered, and the filtrate is concentratedto provide the isocyanate.

Cyclic acetals of formula 4 are commercially available or can beprepared by methods known in the art.

The Piperidine Compounds where X is O and R₄ is —OH can also be obtainedby the illustrative method shown below in schemes 1.3 and 1.4:

where R₁, R₂, R₃, n, m, and p are as defined above, L is a halogen, andNP is a nitrogen protecting group (see, for example, T. W. Greene etal., Protective Groups in Organic Synthesis 494-653 (3d ed. 1999).

To a solution of t-BuLi (1.7M in heptane, 18.4 mL, 31.3 mmol) or n-BuLi(1.6M in heptane, 19.5 mL, 31.3 mmol) in ether (30 mL) is added dropwisea solution of a compound of formula 2a-d (31.3 mmol) in ether (20 mL) at−78° C. under a nitrogen atmosphere. The resulting solution is stirredat −78° C. for about 1 hour. To the resulting solution is added dropwisea compound of formula 5 (25.0 mmol) dissolved in ether (20 mL) at −78°C. and the resulting mixture is allowed to stir at about −50° C. for 3h. The reaction mixture is then quenched with aqueous NH₄Cl at 0° C. andthe reaction mixture is extracted with ether. The organic portions arecombined, dried (Na₂SO₄), and concentrated under reduced pressure toprovide a residue that can be chromatographed using flash chromatographyon a silica gel column eluted with ethyl acetate/hexane (gradientelution 30/70 to 70/30) to provide a compound of formula 6a-d. Thenitrogen protecting group is then removed to provide a compound offormula 7a-d, respectively. The compound of formula 7a-d is then reactedwith an isocyanate of formula R—NCO to provide the compound of formula3a-d, as shown below in scheme 1.4:

where Ar₂, R₁, R₂, R₃, n, m, and p are as defined above.

To a solution of a compound of formula 7a-d (1 mmol) in DCM (1 mL) isadded dropwise a solution of isocyanate Ar₂-NCO (1 mmol) in DCM (1 mL)at the about 25° C. The resultant mixture is allowed to stir at 25° C.for 3 h and concentrated under reduced pressure to provide a residuethat can be chromatographed using a silica gel column eluted with ethylacetate/hexane (gradient elution 10/90 to 70/30) to provide a compoundof formula 3a-d.

A compound of formula 5 is commercially available or can be prepared byprotecting the nitrogen atom of a compound of formula 8, shown below:

Compounds of formula 8 are commercially available or can be prepared bymethods known in the art.

Any nitrogen protecting group known in the art can be used to protectthe nitrogen atom in the compound of formula 8. Suitable protectinggroups are described in T. W. Greene et al., Protective Groups inOrganic Synthesis, 494-653 (3d ed. 1999). Isocyanates of formula Ar₂-NCOare commercially available or can be prepared as described above.

5.6.1.2 Methods for Making Piperidine Compounds Where X is S and R₄ is—OH

The Piperidine Compound where X is S and R₄ is —OH can be obtained by amethod analogous to that described above in Scheme 1.1 to provide thePiperidine Compounds where X is O and R₄ is —OH (3a-d) except that acompound of formula 9, shown below,

where R₃ and m are as defined above, is used in place of compound 1.

The compound of formula 9 can be obtained by a method analogous to thatdescribed above in Scheme 1.2 to provide 1 except that an isothiocyanateof formula Ar₂-NCS is used in place of the isocyanate Ar₂-NCO.

Isothiocyanates are commercially available or can be prepared byreacting an amine of formula Ar₂NH₂ with thiophosgene as shown in thescheme below (See, e.g., Tett. Lett., 41(37), 7207-7209 (2000); Org.Prep. Proced., Int., 23(6), 729-734 (1991); J. Heterocycle Chem., 28(4),1091-1097 (1991); J. Fluorine Chem., 41(3), 303-310 (1988); and Tett.Lett., 42(32), 5414-5416 (2001).

Alternatively, isothiocyanates of formula Ar₂-NCS can be prepared byreacting an amine of formula Ar₂NH₂ with carbon disulfide in thepresence of triethylamine (TEA) in THF, followed by reaction withhydrogen peroxide and hydrochloric acid in water as shown in the schemebelow (See, e.g., J. Org. Chem., 62(13), 4539-4540 (1997)).

The Piperidine Compound where X is S and R₄ is —OH can be obtained by amethod analogous to that described above in Schemes 1.3 and 1.4 toprovide the Piperidine Compounds where X is O and R₄ is —OH (3a-d)except that an isothiocyanate of formula Ar₂-NCS is used in place of theisocyanate of formula Ar₂-NCO.

5.6.1.3 Methods for Making Piperidine Compounds Where X is N—CN and R₄is —OH

The Piperidine Compound where X is N—CN and R₄ is —OH can be obtained asshown below in scheme 1.5:

where Ar₁, Ar₂, R₃ and m are as defined above.

A compound of formula 10 is reacted with an amine of formula Ar₂—NH₂ inan aprotic organic solvent such as diethyl ether, di-n-propyl ether,THF, DCM, or toluene at a temperature of from about 25° C. to about thereflux temperature of the solvent for a period of from about 0.5 h toabout 24 h to provide the Piperidine Compound where X is N—CN and R₄ is—OH. In one embodiment, the aprotic organic solvent is di-n-propylether. In another embodiment, a reaction mixture of di-n-propyl ether, acompound of formula 10 and the amine of formula Ar₂—NH₂ is heated at atemperature of about 70° to about 80° C. In another embodiment, thereaction mixture of di-n-propyl ether, a compound of formula 10 and theamine of formula Ar₂—NH₂ is heated at a temperature of about 75° C. forabout 12 h.

The compound of formula 10 can be obtained as shown below in scheme 1.6:

where Ar₁ is defined above for the Piperidine Compounds.

A compound of formula 7a-d is reacted with diphenyl cyanocarbonimidate35 (commercially available from Sigma-Aldrich, St. Louis, Mo.) in anaprotic solvent such as diethyl ether, di-n-propyl ether, THF, DCM, ortoluene to provide the compound of formula 10. In one embodiment, theaprotic solvent is DCM and the reaction mixture of the compound offormula 7a-d and diphenyl cyanocarbonimidate 35 is allowed to react atabout 25° C. In another embodiment, the aprotic solvent is toluene andthe reaction mixture of the compound of formula 7a-d and diphenylcyanocarbonimidate 35 is allowed to react at about 110° C. The compoundof formula 7a-d and diphenyl cyanocarbonimidate 35 is typically allowedto react for a period of about 0.5 h to about 24 h. Typically thecompound of formula 10 is used without further purification.

The compounds of formula 7a-d can be obtained as described above insection 5.6.1.1.

5.6.1.4 Methods for Making Piperidine Compounds Where X is N—OH and R₄is —OH

The Piperidine Compound where X is N—OH and R₄ is —OH can be prepared bya method analogous to that described above in Scheme 1.1 to provide thePiperidine Compounds where X is O and R₄ is —OH (3a-d) except that acompound of formula 11, shown below,

where R₃ and m are as defined above, R is Ar₂, and P is anoxygen/hydroxyl protecting group, is used in place of compound 1followed by removal of the oxygen/hydroxyl protecting group.

The compound of formula 11 can be obtained as shown below in scheme 1.7:

where R₃ and m are as defined above, R is Ar₂, and OP is anoxygen/hydroxyl protecting group.

A compound of formula 12 (about 0.3 mmol) is reacted with hydroxylamine(50 weight percent in water, about 5.8 mmol) in about 1.5 mL of ethanolwith stirring at a temperature of about 80° C. for about 2 h. Themixture is then concentrated under reduced pressure to provide acompound of formula 13. The hydroxyl group of the compound of formula 13is then protected using an oxygen/hydroxyl protecting group to providethe compound of formula 11. An oxygen/hydroxyl protecting group known inthe art can be used to protect the oxygen atom in the compound offormula 13. Suitable oxygen/hydroxyl protecting groups are disclosed inT. W. Greene et al., Protective Groups in Organic Synthesis 17-200 (3ded. 1999). In one embodiment, the compound of formula 11 is furthertreated using column chromatography or recrystallized.

The compound of formula 12 can be obtained as shown below in scheme 1.8:

where R₃ and m are as defined above and R is Ar₂.

A solution of a compound of formula 9 (about 0.6 mmol), obtained asdescribed above, in DCM is reacted with iodomethane (about 0.9 mmol) inabout 3 mL of tetrahydrofuran with stirring at about 25° C. for about 12h. Excess iodomethane is removed from the mixture under reducedpressure. A solution of triethylamine (about 1.74 mmol) in about 2.5 mLof ethyl acetate is then added to the mixture and the mixture is allowedto stir for about 2 h. The mixture is then concentrated under reducedpressure to provide the compound of formula 12 that can then be furthertreated if desired. In one embodiment, the compound of formula 12 isfurther treated using column chromatography or recrystallization.

5.6.1.5 Methods for Making Piperidine Compounds Where X is N—OR₁₀ and R₄is —OH

The Piperidine Compound where X is N—OR₁₀ and R₄ is —OH can be obtainedby a method analogous to that described above in Scheme 1.1 to providethe Piperidine Compounds where X is O and R₄ is —OH (3a-d) except that acompound of formula 14, shown below,

where R₃, R₁₀ and m are as defined above and R is Ar₂ is used in placeof compound 1.

The compound of formula 14 can be prepared by reacting the compound offormula 13, obtained as described above in Scheme 1.7, withL-(C₁-C₄)alkyl, where L is —I, —Br, —Cl, or —F in the presence of sodiumhydride in DMF at about 25° C. In one embodiment, L is —I or —Br.

5.6.1.6 Methods for Making Piperidine Compounds Where R₄ is a GroupOther Than —OH

The Piperidine Compounds where R₄ is -halo, —OCF₃, —(C₁C₆)alkyl, —CH₂OH,—CH₂Cl, —CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃, —OR₁₀, —SR₁₀, —COOH,—COOR₁₀, —C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀, —NHC(O)R₁₃, —SO₂R₁₀,—CON(R₁₃)₂ or —NO₂ can be obtained from the Piperidine Compounds whereR₄ is —OH.

The Piperidine Compounds where R₄ is —F can be obtained by reacting aPiperidine Compound where R₄ is —OH with fluorinating reagents such asDAST, Deoxo-Fluor, SF₄, HF, KF, CsF, Yarovenko's reagent, Ishikawa'sreagent, according to the procedure described in M. Schlosser et al.,Tetrahedron 52(24):8257-8262 (1996).

The Piperidine Compounds where R₄ is —Cl can be obtained by reacting aPiperidine Compound where R₄ is —OH with SOCl₂ or PCl₅ according to theprocedure described in J. Amer. Chem. Soc. 120(4):673-679 (1998) or withCH₃COCl according to the procedure described in Tett. Lett.41(47):9037-9042 (2000).

The Piperidine Compounds where R₄ is —Br can be obtained by reacting aPiperidine Compound where R₄ is —OH with pyridine and SOBr₂ according tothe procedure described in J. Organometallic Chemistry 627(2):179-88(2001) or by reacting a Piperidine Compound where R₄ is —OH withpyridine and PPh₃/Br₂ according to the procedure described in J. Amer.Chem. Soc. 112 (9):3607-14 (1990).

The Piperidine Compounds where R₄ is —I can be obtained by reacting aPiperidine Compound where R₄ is —OH with HI in acetic anhydrideaccording to the procedure described in J. Amer. Chem. Soc.87(3):539-542 (1965).

The Piperidine Compounds where R₄ is —CH₃ can be obtained by reacting aPiperidine Compound where R₄ is —OH with PCl₅ and CH₃TiCl₃ according tothe procedure described in Angewandte Chemie, 92(11), 933-4 (1980).

The Piperidine Compounds where R₄ is —(C₁-C₆)alkyl can be obtained byreacting a Piperidine Compound where R₄ is —OH with p-toluenesulfonicacid in toluene followed by n-butyl lithium and X—(C₁-C₆)alkyl, where Xis a halogen, according to the procedure described in Charles J.Barnett, et al., J. Org. Chem., 54(20) 4795-4800 (1989) followed byhydrogenating the product according to the procedure described in ThomasE. D'Ambra et al., J. Org. Chem., 54(23) 5632-5 (1989) as describedbelow.

The Piperidine Compounds where R₄ is —CH₂OH can be obtained by reactinga Piperidine Compound where R₄ is —COOH with LiAlH₄ according toprocedures known in the art. The Piperidine Compounds where R₄ is —CH₂OHcan be obtained by reacting a Piperidine Compound where R₄ is —C(O)Hwith NaBH₄ according to procedures known in the art.

The Piperidine Compounds where R₄ is —COOH can be obtained by reacting aPiperidine Compound where R₄ is —CN with KOH according to proceduresknown in the art.

The Piperidine Compounds where R₄ is —CN can be obtained by reacting aPiperidine Compound where R₄ is —OH with KCN and SOCl₂ according to theprocedure described in Armyanskii Khimicheskii Zhurnal. 30(9):723-727(1977).

The Piperidine Compounds where R₄ is —C(O)H can be obtained by reactinga Piperidine Compound where R₄ is —CN with di-iso-butylaluminum hydride(DIBAL-H) according to procedures known in the art.

The Piperidine Compounds where R₄ is —OCF₃ can be obtained by reacting aPiperidine Compound where 4 is —OH with CS₂; methyl idodide; andbromosuccinimide and pyridined/HF in DCM according to the proceduredescribed in Chemical Communications (Cambridge) 3:309-310 (1997) orBulletin of the Chemical Society of Japan, 73(2:471-484 (2000).

The Piperidine Compounds where R₄ is —CH₂Cl can be obtained by reactinga Piperidine Compound where R₄ is —CH₂OH, obtained as described above,with PCl₅ according to the procedure described in J. Amer. Chem. Soc.,120(4):673-679 (1998).

The Piperidine Compounds where R₄ is —CH₂Br can be obtained by reactinga Piperidine Compound where R₄ is —CH₂OH, obtained as described above,with SOBr₂ according to the procedure described in J. Organomet. Chem.,627(2):179-188 (2001) or with PPh₃/Br₂ according to the proceduredescribed in J. Amer. Chem. Soc., 112(9):3607-3614 (1990).

The Piperidine Compounds where R₄ is —CH₂F can be obtained by reacting aPiperidine Compound where R₄ is —CH₂OH, obtained as described above,with 1 eq. of DAST according to the procedure described in M. Schlosseret al., Tetrahedron 52(24):8257-8262 (1996) and Organic Letters.3(17):2713-2715 (2001).

The Piperidine Compounds where R₄ is —CH₂F can be obtained by reacting aPiperidine Compound where R₄ is —CH₂OH, obtained as described above,with PPh₃/I₂ according to the procedure described in Organic ProcessResearch and Development 6(2):190-191 (2002).

The Piperidine Compounds where R₄ is —CH(halo)₂ can be obtained byreacting a Piperidine Compound where R₄ is —C(O)H, obtained as describedabove, with (F₃CSO₂)₂O followed by Mg(halo)₂ in CS₂ according to theprocedure described in Synthesis 12:1076-1078 (1986).

The Piperidine Compounds where R₄ is —CHF₂ can also be obtained byreacting a Piperidine Compound where R₄ is —C(O)H, obtained as describedabove, with 2 eq. of DAST according to the procedure described in M.Schlosser et al., Tetrahedron 52(24):8257-8262 (1996) and OrganicLetters. 3(17):2713-2715 (2001).

The Piperidine Compounds where R₄ is —CF₃ can be obtained by reacting aPiperidine Compound where R₄ is —C(O)H, obtained as described above,with copper (I) iodide and sodium trifluoroacetate according to theprocedure described in U.S. Pat. No. 4,866,197 to Bauman.

The Piperidine Compounds where R₄ is —OR₁₀ can be obtained by reacting aPiperidine Compound where R₄ is —OH, obtained as described above, withR₁₀—X where X is a halogen in the presence of NaOH according to theprocedure described in European Journal of Medicinal Chemistry24(4):391-396 (1989).

The Piperidine Compounds where R₄ is —SR₁₃ can be obtained by reacting aPiperidine Compound where R₄ is —OH, obtained as described above, withR₁₃—SH according to the procedure described in U.S. Pat. No. 4,409,229to Ong et al. or Journal of Medicinal Chemistry 24(1):74-79 (1981).

The Piperidine Compounds where R₄ is —COOR₁₀ can be obtained byesterifying a Piperidine Compound where R₄ is —COOH, obtained asdescribed above, with R₁₀—OH. Methods to esterify carboxylic acids areknown in the art.

The Piperidine Compounds where R₄ is —OC(O)R₁₀ can be obtained byreacting a Piperidine Compound where R₄ is —OH, obtained as describedabove, with R₁₀C(O)Cl according to the procedure described in EuropeanJournal of Medicinal Chemistry 24(4):391-396 (1989). The acid chlorides,R₁₀C(O)Cl, can be prepared from the corresponding carboxylic acid,R₁₀COOH, using procedures known in the art.

The Piperidine Compounds where R₄ is —NHC(O)R₁₃ can be obtained byreacting a Piperidine Compound where R₄ is —OH with R₁₀CN in thepresence of H₂SO₄ followed by K₂CO₃ in DCM as described in Bioorganicand Medicinal Chemistry Letters 10(17):2001-2014 (2000).

The Piperidine Compounds where R₄ is —OC(O)NH₂ can be obtained byreacting a Piperidine Compound where R₄ is —OH with Cl₃CCONCO in DCM at0° C. with stirring for about 2 h and then adding to the resultingmixture K₂CO₃ in methanol-water and allowing the resulting mixture tostir for about 4 h at 0° C. and about 2 h at about 25° C. according tothe procedure described in Christopher P. Holmes et al, J. Org. Chem.,54(1):98-108 (1989).

The Piperidine Compounds where R₄ is —OC(O)NHR₁₀ can be obtained byreacting a Piperidine Compound where R₄ is —OH with an isocyanate offormula R₁₀NCO in refluxing THF for about 24 h at about 25° C. accordingto the procedure described in Andre Hallot et al, J. Med. Chem.,29(3):369-375 (1986).

The Piperidine Compounds where R₄ is —SO₂R₁₀, —NO₂, —CN, —COR₁₀,—COOR₁₀, and CON(R₁₃)₂ can be prepared by the illustrative methodsdescribed below.

A compound of formula 15 is reacted with a compound of formula 16a-d inthe presence of a base according to the procedure described in Journalof Heterocycle Chemistry, 23(1):73-75 (1986) or Organic Chemistry andProcedures International 28(4):478-480 (1996) to provide a compound offormula 17a-d, as described below in scheme 1.9:

where R₁, R₂, R₃, n, m, and p are as defined above; Y is —SO₂R₁₀, —NO₂,—CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂; and NP is a nitrogen protectinggroup.

The nitrogen protecting group is then removed from the compound offormula 17a-d to provide a compound of formula 18a-d. Any nitrogenprotecting group known in the art can be used to protect the nitrogen inthe compound of formula 15.

To provide the Piperidine compounds of formula I where X is O and R₄ is—SO₂R₁₀, —NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂, the compound offormula 18a-d is then reacted with an isocyanate of formula R—NCOaccording to a procedure analogous to that described above in scheme 1.4and described below in Scheme 1.10:

where R₁, R₂, R₃, n, m, and p are as defined above; Y is —SO₂R₁₀, —NO₂,—COR₁₀, or —CON(R₁₃)₂; and R is Ar₂.

A compound of formula 18a-d is reacted with a compound of formula R—NCOaccording to a procedure analogous to that described above in Scheme1.4.

To provide the Piperidine Compounds where X is S and R₄ is —SO₂R₁₀,—NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂, the compound of formula 18a-dis reacted with an isothiocyanate of formula R—NCS according to aprocedure analogous to that described above in Section 5.6.1.2.

To provide the Piperidine Compounds where X is N—CN and R₄ is —SO₂R₁₀,—NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂, the compound of formula 18a-dis reacted with diphenyl cyanocarbonimidate 35 and then an amine offormula R—NH₂ according to a procedure analogous to that described abovein Section 5.6.1.3.

To provide the Piperidine Compounds where X is N—OH and R₄ is —SO₂R₁₀,—NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂, the Piperidine Compound whereX is S and R₄ is —SO₂R₁₀, —NO₂, —CN, —COR₁₀, —COOR₁₀, and CON(R₁₃)₂ isreacted with methyl iodide according to a procedure analogous to thatdescribed above in scheme 1.8 to provide a compound of formula 19,

where Ar₁, R₃, m, and Y are as defined above and R is Ar₂.

The compound of formula 19 is then reacted with hydroxylamine in ethanolaccording to a procedure analogous to that described above in Scheme 1.8to provide the Piperidine Compounds where X is N—OH and R₄ is —SO₂R₁₀,—NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂.

To provide the Piperidine Compounds where X is N—OR₁₀ and R₄ is —SO₂R₁₀,—NO₂, —CN, —COR₁₀, —COOR₁₀, or CON(R₁₃)₂, the Piperidine Compound whereX is NOH and R₄ is —SO₂R₁₀, —NO₂, —CN, —COR₁₀, —COOR₁₀, and CON(R₁₃)₂ isreacted with X—(C₁-C₄)alkyl, where X is —I, —Br, —Cl, or —F in thepresence of triethylamine according to a procedure analogous to thatdescribed above in Section 5.6.1.6.

The compound of formula 15 is commercially available or can be preparedby methods known in the art.

The compounds of formula 16a-d where Y is —SO₂R₁₀ can be obtained byreacting a compound of formula 16a-d, where Y is a halogen, with R₁₀SO₂Haccording to the procedure described in J. Org. Chem. 67(13):4387-4391(2002) or international publication no. WO 02/48098.

The compounds of formula 16a-d where Y is —CN can be obtained byreacting a compound of formula 16a-d, where Y is a halogen, withpotassium cyanide according to the procedure described in Farmaco45(9):945-953 (1990).

The compounds of formula 16a-d where Y is —COOR₁₀ can be obtained byreacting a compound of formula 16a-d, where Y is a halogen, with (a)potassium cyanide, (b) water, and (c) R₁₀OH and SO₂Cl according to theprocedure described in Farmaco 45(9):945-953 (1990).

The compounds of formula 16a-d where Y is —COR₁₀ can be obtained byreacting a compound of formula 16a-d, where Y is a halogen, withR₁₀C(O)H and trimethylsilyl cyanide according to the procedure describedin international publication no. WO 01/81333.

The compounds of formula 16a-d where Y is —CON(R₁₃)₂ can be obtained byreacting a compound of formula 16a-d, where Y is a halogen, with (a)potassium cyanide, (b) water, and (c) NH(R₁₃)₂ and SO₂Cl according tothe procedure described in Farmaco 45(9):945-953 (1990).

The compounds of formula 16a-d where Y is —NO₂ can be obtained byreacting a compound of formula 2a-d where X is —CH₃ with NaNH₂ in liquidNH₃ followed by CH₃CH₂CH₃—ONO₂ at a temperature of less than −33° C. toprovide a nitronate that is then reacted under acidic condition toprovide the compound of formula 16a-d where Y is —NO₂ according to theprocedure described in H. Feuer et al., J. Am. Chem. Soc.91(7):1856-1857 (1969) and as described in scheme 1.11 below, where R₁,R₂, n and p are as defined above.

The compounds of formula 16a-d where Y is -halo are commerciallyavailable or can be prepared by methods known in the art.

Certain Piperidine Compounds can have one or more asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. APiperidine Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses PiperidineCompounds and their uses as described herein in the form of theiroptical isomers, diastereomers, and mixtures thereof, including aracemic mixture. Optical isomers of the Piperidine Compounds can beobtained by known techniques such as chiral chromatography or formationof diastereomeric salts from an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of a PiperidineCompound can be replaced by an isotope of the hydrogen, carbon or otheratoms. Such compounds, which are encompassed by the invention, areuseful as research and diagnostic tools in metabolism pharmacokineticstudies and in binding assays.

5.6.1.7 Methods for Installing R₂ Groups on Ar₁ When R₂ is O

The conversion of a halide, L to a vinyl group via a Suzukicross-coupling reaction is exemplified in scheme 1.12 below, where R₁,R₂, R₄ and p are as defined above, L is defined as -halo, and P is anitrogen protecting group known in the art. While this exampledemonstrates the conversion when L is in the 5-position of the pyridylring of 20, the transformation can be carried out when L is in otherpositions on the aryl ring as well. Moreover, the same technique can beused when Ar_(r) is another pyridyl ring, pyrimidinyl, pyrazinyl orpyridazinyl ring.

To a degassed DMF solution of compound 20 (1.6 mmol) in a 100 mL roundbottom flask, is added CsF (3.2 mmol), di-n-butyl vinyl boronic ester(0.388 mL, 1.76 mmol) and palladium diphenylphosphinoferrocenedichloride (Pd(DPPF)₂Cl₂, 0.128 mmol). The resulting mixture is stirredat 100° C. for 14 hr, then cooled to a temperature of about 25° C. anddiluted with 100 mL ethyl acetate, which was washed with brine (3×50mL). The organic layer was isolated, dried, and concentrated underreduced pressure. Silica gel column chromatography gives the product,21.

Other techniques for the installation of the vinyl group are shown inschemes 1.13a and 1.13b. In scheme 1.13a, the first step involves theoxidation of a benzylic alcohol to an aldehyde. This is followed by aWittig olefination, to yield the vinyl group. Once again, while thisexample demonstrates the conversion when the starting benzylic alcoholis in the 5-position of a pyridyl ring, similar conversions can becarried out at other positions. Moreover, the same technique can be usedwhen Ar_(r) is another pyridyl ring, pyrimidinyl, pyrazinyl orpyridazinyl.

To a 500 mL round-bottom flask, manganese oxide (0.50 mol) is added to asolution of 22 (50.0 mmol) in anhydrous CH₂Cl₂ (150 mL). The resultingmixture is stirred at a temperature of about 25° C. for 48 h and thenthe reaction mixture is filtered through CELITE and concentrated. Theresulting mixture is chromatographed by silica gel column chromatographyeluting with a gradient of ethyl acetate (0%-40%)/hexanes to providealdehyde 23.

To a cooled 0° C., stirred slurry of methyltriphenylphosphonium bromide(10.0 g) in toluene (200 mL) is added potassium t-butoxide (3.07 g)portionwise to produce a yellow slurry. After 1 hr, the reaction mixtureis cooled to −20° C., and 23 (22.72 mmol) dissolved in tetrahydrofuran(6 mL) is added dropwise to produce a purple colored slurry. Thereaction mixture is heated to 0° C. and stirred for additional 1 hr.Then the reaction mixture is treated with saturated aqueous brine (150mL) and diluted with ethyl acetate (200 mL). The resulting organic layeris washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting product ischromatographed by silica gel column chromatography column, eluting witha gradient of ethyl acetate (0%-10%)/hexanes to provide product 24.

In scheme 1.13b, the first step involves the reduction of a benzylicketone to a hydroxyl. This is followed by a dehydration reaction toyield the vinyl group. Once again, while this example demonstrates theconversion when the starting benzylic ketone is in the 5-position of apyridyl ring, similar conversions can be carried out at other positions.Moreover, the same technique can be used when Ar_(r) is another pyridylring, pyrimidinyl, pyrazinyl or pyridazinyl.

To a well-stirred suspension of 23 (665 g, 3.5 mol) in methanol (3.5 L)at 0° C. is added sodium borohydride (66.21 g, 1.75 mol) portionwise ata rate such that the reaction mixture temperature does not exceed 5° C.After the addition is complete, the reaction mixture is warmed to atemperature of about 25° C. and stirred an additional 1 h. The reactionmixture is concentrated under reduced pressure and the residue mixedwith 2 L diethyl ether and 2 L 1N HCl. The layers are separated and theaqueous layer extracted twice with diethyl ether (250 mL for eachextraction). The organic portions are combined, dried (MgSO₄), andconcentrated under reduced pressure to provide 23a.

To a solution of 23a (311 g, 1.62 mol) in chlorobenzene (3 L) is addedp-toluene sulfonic acid (431 g, 2.5 mol). The reaction mixture is heatedto reflux, about 140° C., and water is removed concurrently. At thecompletion of the reaction, the mixture is concentrated under reducedpressure to about 500 mL, diluted with 2 L of water, and extracted threetimes with ethyl acetate (1 L for each extraction). The organic portionsare combined, dried (Na₂SO₄), and concentrated under reduced pressureunder mild heating to provide a residue. The residue is added to 500 mLof methylene chloride and applied to the top of column packed with 2 kgsilica eluted with a 0% to 10% gradient of ethyl acetate in hexane toprovide 24.

Vinyl groups are highly versatile, because they are a synthetic handlethat can be further modified. It is well known in synthetic organicchemistry that olefin hydrolysis yields a benzylic hydroxyl group,hydroboration gives a primary hydroxyl group, ozonolysis gives analdehyde or ketone, oxidation gives a carboxylic acid, olefin metathesisextends the chain, and dihydroxylation gives a 1,2-diol. Many additionalolefin functionalization techniques are available to those skilled inorganic synthesis. Once functionalized, the group can undergo furthertransformations. Exemplified in scheme 1.14 is the vinyl group of 21undergoing an asymmetric dihydroxylation.

In a 100 mL round bottom flask, AD-mix α (0.5 g) is added to a mixtureof t-butanol and water (2 mL/2 mL) and the mixture is stirred at atemperature of about 25° C. for 0.5 hr, and then cooled to 0° C. Thissolution is quickly poured into another ice chilled flask, whichcontains compound 21 (0.41 mmol). The mixture is stirred vigorously inan ice bath for 96 h, and then diluted with ethyl acetate (50 mL) and 2mL saturated Na₂S₂O₅. The ethyl acetate layer is isolated, dried, andconcentrated under reduced pressure with a rotary evaporator to provide25a. The other enantiomer, can be synthesized by the reaction of 21 withAD-mix β to yield 25b. As demonstrated in scheme 1.14, thestereochemistry (R or S) of the resulting diol, is dependent upon thechirality of the ligand used in the AD mix as described in Sharpless etal., J. Org. Chem. 57:2768-2771 (1992). AD-mix is composed of thefollowing components: potassium osmate (K₂OsO₂(OH)₄), potassiumferricyanide (K₃Fe(CN)₆), potassium carbonate (K₂CO₃), and the chiralligands are shown in scheme 1.15.

The racemic diol, 25c, can be synthesized by methods known in the art,using osmium tetroxide (OSO₄) and N-methyl morpholine N-oxide (NMO) inan aqueous acetone solution.

5.6.2 Methods for Making Compounds of Formula I Where W is C and theDashed Line is Present

The compounds of formula 1 where W is C and the dashed line is present,i.e., “Tetrahydropiperidyl Compounds,” can be made using conventionalorganic synthesis or by the following illustrative methods shown in theschemes below.

5.6.2.1 Methods for Making the Tetrahydropiperidyl Compounds Where X isO

The Tetrahydropiperidyl Compounds where X is O can be obtained by thefollowing illustrative method shown below in Schemes 2.1 and 2.2, whereR₃, Ar₂, and m are as defined above.

Referring to scheme 2.1 above, compound 1 (about 3.6 mmol) is dissolvedin THF (100 mL) and the resulting solution cooled to −78° C. To thecooled solution is added LiHMDS (8.75 mmol) and the reaction mixture isstirred at −78° C. for 2 h. Compound 26 (about 3.6 mmol, Sigma-Aldrich)is then added to the reaction mixture and the reaction mixture isstirred at −78° C. for 2 h. The reaction mixture is then allowed to warmto 25° C. and concentrated under reduced pressure to provide a compoundof formula 27.

The compound of formula 27 is then reacted with a compound of formula28a-d to provide the Tetrahydropiperidyl Compound where X is O as shownbelow in scheme 2.2:

where R₁, R₂, R₃, Ar₁, n, m, and p are as defined above.

Pd(PPh₃)₄ (0.11 mmol) is dissolved in THF (about 50 mL) and the compoundof formula 27 (about 2.2 mmol) is added to the resulting solutionfollowed by a compound of formula 28a-d (about 6.6 mmol as a 0.5Msolution in THF).

The reaction mixture is then heated for 1 h at the reflux temperature ofthe solvent. The reaction mixture is allowed to cool to 25° C. andconcentrated under reduced pressure to provide the TetrahydropiperidylCompound where X is O. The Tetrahydropiperidyl Compound where X is O canbe further treated if desired. In one embodiment, theTetrahydropiperidyl Compound where X is O is chromatographed usingsilica gel column chromatography followed by trituration with ethylacetate.

Where m=1, R₃ is bonded to an sp3 carbon, and 27 is either racemic or amixture of enantiomers, the resulting Tetrahydropiperidyl Compound inscheme 2.2 will also be racemic or an enantiomeric mixture. If a singlestereoisomer is desired, it is possible to use chiral separationtechniques known in the art, such as chiral chromatography or chiralresolution, to isolate a single isomer.

Another technique that can be used to couple the tetrahydropiperidylgroup and Ar₁ is the Suzuki cross-coupling reaction. This isaccomplished by a catalyst mediated reaction of 2a with thetetrahydropiperidyl borane, 29 as exemplified in scheme 2.3 below. Whilethe reaction shown has Ar₁ as a pyridyl group, the same technique can beused when Ar_(r) is a pyrazinyl (2b), pyrimidinyl (2c), pyridazinyl (2d)or other pyrazinyl rings.

A 150 mL sealed vessel is charged with 2a (3.37 mmol), 29 (4.04 mmol),Pd(PPh₃)₂Cl₂ (0.27 mmol), potassium carbonate (6.40 mmol), and a mixtureof DME/EtOH/H₂O (8 mL/4 mL/8 mL). The resulting mixture is purged withnitrogen, sealed, and heated at 90° C. with a vigorous stirring. After 2hrs, the reaction mixture is cooled to a temperature of about 25° C. anddiluted with EtOAc (50 mL). The organic layer is washed with brine,dried (Na₂SO₄), and concentrated under reduced pressure. The residue ischromatographed by silica gel column chromatography with a gradient ofethyl acetate (0%-30%)/hexanes to provide product 30.

The boronate ester, 29 can be synthesized by the method demonstratedbelow in scheme 2.4.

Bis(pinacolato)diboron (333.6 mmol), diphenylphosphino ferrocene (9.1mmol), palladium diphenylphosphinoferrocene dichloride (1:1 complex withdichloromethane) (9.1 mmol), and potassium acetate (909.9 mmol) aresuspended in dry dioxane (900 mL) under argon with mechanical stirring.4-(Nonafluorobutane-1-sulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (303.3 mmol) in dry dioxane (500 mL) is added andthe mixture is heated to 85° C. for 16 h. The mixture is cooled,filtered through CELITE, and the filter cake is washed withdichloromethane (2 L). The filtrate is concentrated under reducedpressure to provide a black solid. This is adsorbed onto silica gel (250g) and applied to the head of a 4″ silica gel column, and it is theneluted with hexanes (5 L) followed by 20:1 hexanes:ethyl acetate, andfinally ethyl acetate (10 L) to yield 29.

5.6.2.2 Methods for Making the Tetrahydropiperidyl Compounds Where X isS

The Tetrahydropiperidyl Compounds where X is S can be obtained bymethods analogous to that described above in schemes 2.1 and 2.2 toprovide the Tetrahydropiperidyl Compounds where X is O, except that anisothiocyanate of formula Ar₂-NCS is used in place of the isocyanateAr₂-NCO.

5.6.2.3 Methods for Making the Tetrahydropiperidyl Compounds Where X isN—CN

The Tetrahydropiperidyl Compounds where X is N—CN can be obtained asshown below in Schemes 2.5 and 2.6 where Ar₂, R₃, and m are as definedabove.

A ketal of formula 31 (about 14 mmol) is reacted with an amine offormula Ar—NH₂ (about 14 mmol) in an aprotic organic solvent (about 7mL) such as diethyl ether, di-n-propyl ether, THF, DCM, or toluene at atemperature of from about 25° C. to about the reflux temperature of thesolvent for a period of from about 0.5 h to about 24 h. The reactionmixture is then concentrated under reduced pressure to provide acompound of formula 32. In one embodiment, the aprotic organic solventis di-n-propyl ether. In another embodiment, a reaction mixture ofdi-n-propyl ether, a compound of formula 31 and the amine of formulaAr—NH₂ is heated at a temperature of about 70° to about 80° C.

The compound of formula 32 is then dissolved in THF (about 20 mL). About1N HCl in acetic acid (about 30 mL) is added to the THF solution of thecompound of formula 32 and the resulting mixture is heated at the refluxtemperature of the solvent. Typically, the reaction mixture is heated atthe reflux temperature of the solvent for about 3 h. The reactionmixture is then cooled and concentrated under reduced pressure toprovide a residue that is dissolved in DCM. The DCM solution is thenextracted with aqueous Na₂CO₃. The aqueous and organic layers areseparated and the aqueous layer is extracted three times with DCM. Theorganic portions are combined, dried (MgSO₄), and concentrated underreduced pressure to provide a compound of formula 33. The compound offormula 33 can be further treated if desired. In one embodiment, thecompound of formula 33 is chromatographed using silica gel columnchromatography.

The compound of formula 33 (about 3.6 mmol) is then dissolved in THF(about 100 mL) and the resulting solution cooled to about −78° C. To thecooled solution is added LiHMDS (about 8.75 mmol) and the reactionmixture is stirred at about −78° C. for about 2 h. A compound of formula26 (about 3.6 mmol, Sigma-Aldrich) is then added to the reaction mixtureand the reaction mixture stirred at about −78° C. for about 2 h. Thereaction mixture is then allowed to warm to about 25° C. andconcentrated under reduced pressure to provide a compound of formula 34.

The compound of formula 34 is then reacted with a compound of formula28a-d as shown below in scheme 2.6 below to provide theTetrahydropiperidyl Compound where X is N—CN.

where Ar₂, R₁, R₂, R₃, n, m, and p are as defined above.

Pd(PPh₃)₄ is dissolved in THF (about 50 mL) and the compound of formula34 (about 2.2 mmol) is added to the resulting mixture followed by acompound of formula 28a-d (about 6.6 mmol as a 0.5M solution in THF).The reaction mixture is then heated for about 1 h at the refluxtemperature of the solvent. The reaction mixture is allowed to cool toabout 25° C. and concentrated under reduced pressure to provide theTetrahydropiperidyl Compound where X is N—CN. The TetrahydropiperidylCompound where X is N—CN can be further treated if desired. In oneembodiment, the Tetrahydropiperidyl Compound where X is N—CN ischromatographed by silica gel column chromatography.

Where m=1, R₃ is bonded to an sp3 carbon, and 34 is either racemic or amixture of enantiomers, the resulting Tetrahydropiperidyl Compound inscheme 2.6 will also be racemic or an enantiomeric mixtures. If a singlestereoisomer is desired, it is possible to use chiral separationtechniques known in the art, such as chiral chromatography or chiralresolution, to isolate a single isomer.

The compound of formula 31 can be obtained as shown below in scheme 2.7.

where R₃, and m are as defined above.

Compound 4 is reacted with diphenyl cyanocarbonimidate 35(Sigma-Aldrich) in an aprotic solvent such as diethyl ether, di-n-propylether, THF, DCM, or toluene to provide the compound of formula 31. Inone embodiment, the aprotic solvent is DCM and the reaction mixture ofcompound 4 and diphenyl cyanocarbonimidate 35 is allowed to react atabout 25° C. In another embodiment, the aprotic solvent is toluene andthe reaction mixture of compound 4 and diphenyl cyanocarbonimidate 35 isallowed to react at about 110° C. Compound 4 and diphenylcyanocarbonimidate 35 are typically allowed to react for a period ofabout 0.5 h to about 24 h.

The compounds of formula 28a-d can be obtained as described above bymethods known in the art.

5.6.2.4 Methods for Making the Tetrahydropiperidyl Compounds Where X isN—OH

The Tetrahydropiperidyl Compounds where X is N—OH can be obtained in amanner analogous to schemes 2.6 and 2.7 in section 5.6.2.3, which isshown in scheme 2.8.

where Ar₂, R₁, R₂, R₃, n, m, and p are as defined above and P is anoxygen/hydroxyl protecting group.

The method for obtaining the Tetrahydropiperidyl Compounds where X isN—OH as described above in scheme 2.8 is analogous to that describedabove in Schemes 2.5 and 2.6 to provide the TetrahydropiperidylCompounds where X is N—CN except that a compound of formula 38 is usedin place of the compound of formula 34.

The compound of formula 36 can be obtained as described below in scheme2.9.

where Ar₂, R₃, and m are as defined above and P is an oxygen/hydroxylprotecting group.

A compound of formula 40 (about 0.3 mmol) is reacted with hydroxylamine(50 weight percent in water, about 5.8 mmol) in about 1.5 mL of ethanolwith stirring at a temperature of about 80° C. for about 2 h. Themixture is then concentrated under reduced pressure to provide acompound of formula 41. The hydroxyl group of the compound of formula 41is then protected using an hydroxyl protecting group to provide thecompound of formula 36. Any hydroxyl protecting group known in the artcan be used to protect the hydroxyl group in the compound of formula 41.Suitable hydroxyl protecting groups and methods for their removal aredisclosed in T. W. Greene et al, Protective Groups in Organic Synthesis17-200 (3d ed. 1999).

Where m=1, R₃ is bonded to an sp3 carbon, and 38 is either racemic or amixture of enantiomers, the resulting Tetrahydropiperidyl Compound inscheme 2.8 will also be racemic or enantiomeric mixtures. If a singlestereoisomer is desired, it is possible to use chiral separationtechniques known in the art, such as chiral chromatography or chiralresolution, to isolate a single isomer.

The compound of formula 40 can be obtained as shown below in scheme2.10.

where Ar₂, R₃, and m are as defined above.

A solution of a compound of formula 42 (about 0.6 mmol), obtained asdescribed above in section 4.4.2.2, in DCM is reacted with iodomethane(about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at about25° C. for about 12 h. Excess iodomethane is removed from the mixtureunder reduced pressure. A solution of triethylamine (about 1.74 mmol) inabout 2.5 mL of ethyl acetate is then added to the mixture and themixture is allowed to stir for about 2 h. The mixture is thenconcentrated under reduced pressure to provide the compound of formula40 which can then be further treated if desired. In one embodiment, thecompound of formula 40 is chromatographed using column chromatography orrecrystallized.

5.6.2.5 Methods for Making the Tetrahydropiperidyl Compounds Where X isN—OR₁₀

The Tetrahydropiperidyl Compounds where X is N—OR₁₀ can be obtained byreacting a Tetrahydropiperidyl Compounds where X is N—OH, obtained asdescribed above in Scheme 2.8, with L-(C₁-C₄)alkyl, where L is —I, —Br,—Cl, or —F, in the presence of about 3 eq. of triethylamine in THF, withstirring at about 25° C. for about 12 h or at about 50° C. for about 3h. The reaction mixture is concentrated under reduced pressure toprovide a residue. The residue is then chromatographed using silica gelcolumn chromatography eluted with a gradient elution of from 100:0hexane:ethyl acetate to 25:75 hexane:ethyl acetate to provide theTetrahydropiperidyl Compounds where X is N—OR₁₀. In one embodiment, L is—I or —Br.

5.6.3 Methods for Making Compounds of Formula I Where W is N and theDashed Line is Absent

The compounds of formula I where W is N and the dashed line is absent,i.e., “piperazine Compounds,” can be made using conventional organicsynthesis or by the following illustrative methods shown in the schemesbelow.

5.6.3.1 Methods for Making Piperazine Compounds where X is O and Ar₂ isa Benzothiazolyl Group

Piperazine Compounds where X is O, Ar₂ is a benzothiazolyl group, andR₂₀ is —H, can be obtained by the following illustrative method shown inscheme 3.1:

where Ar₁, R₃, R₈, R₉ and m are as defined above.

A compound of formula 44 (about 2 mmol) is dissolved in an aproticorganic solvent (about 3 mL). To the resulting solution is added acompound of formula 43 (about 2 mmol) and the reaction mixture allowedto stir for about 10 min. The reaction mixture is concentrated underreduced pressure to provide the piperazine Compounds where X is O, Ar₂is a benzothiazolyl group, and R₂₀ is —H. Such piperazine Compounds canbe chromatographed on a silica column eluted with 5:95 ethylacetate:hexane.

The compound of formula 44 can be obtained as shown below in scheme 3.2:

where R₈ and R₉ are as defined above.

A compound of formula 45 (about 0.75 mmol) in an aprotic organic solvent(about 0.04M) is cooled to about 0° C. To the cooled solution is slowlyadded a solution of a compound of formula 46 (about 0.75 mmol) in anaprotic organic solvent (about 0.4M). The reaction mixture is stirred at0° C. for about 5 min. and about 0.75 mmol of triethylamine are added tothe reaction mixture. The reaction mixture is then allowed to warm to atemperature of about 25° C. and concentrated under reduced pressure toprovide the compound of formula 44. The compound of formula 45 iscommercially available, e.g., from Sigma-Aldrich. Compounds of formula46 are commercially available or can be prepared by the followingillustrative method shown below in scheme 3.3:

where R₈ and R₉ are as defined above.

To a stirred solution of aniline 47 (about 74 mmol) and potassiumthiocyanate (about 148 mmol) in about 100 mL of glacial acetic acid isadded dropwise a solution of bromine (about 74 mmol) in about 25 mL ofglacial acetic acid. The flask containing the bromine in acetic acid isthen rinsed with about 15 mL of acetic acid which is combined with thesolution of aniline 47. The reaction mixture is vigorously stirred at atemperature of about 25° C. for between about 2 h and about 24 h. Thereaction mixture is then poured over crushed ice (about 500 mL) and thepH of the resulting mixture adjusted to a value of about 10 usingammonium hydroxide to provide a precipitate. The resulting precipitateis collected by filtration and recrystallized from toluene to providethe compound of formula 46. Compounds of formula 47 are commerciallyavailable or can be prepared by methods known in the art.

The compound of formula 50a-d can be obtained as shown below in scheme3.4:

where R₁, R₂, R₃, m, n, and p are as defined above and L is a halogen.

A compound of formula 49a-d (about 20 mmol) is reacted with a compoundof formula 48 (about 27.5 mmol) in about 15 mL of DMSO in the presenceof triethylamine (about 30 mmol), optionally with heating, for about 24h to provide a compound of formula 50a-d. The compound of formula 50a-dis isolated from the reaction mixture and further treated if desired. Inone embodiment, the compound of formula 50a-d is chromatographed usingcolumn chromatography or recrystallized.

Compounds of formula 48 and 49a-d are commercially available or can beprepared by methods known in the art. The compound of formula 48 where mis 0 and the compound of formula 48 where m is 1 and R₃ is (R)—CH₃ or(S)—CH₃ are commercially available, e.g., from Sigma-Aldrich. In oneembodiment, L is bromide, chloride, or iodide.

Piperazine Compounds where X is O, Ar₂ is a benzothiazolyl group, andR₂₀ is —(C₁-C₄)alkyl can be obtained by the following illustrativemethod shown below in scheme 3.5:

where Ar₁, R₃, R₈, R₉, R₂₀, and m are as defined above and L is ahalogen.

To a solution of a piperazine Compound where X is O, Ar₂ is abenzothiazolyl group, and

R₂₀ is —H (about 1 eq.), obtained as described above in Scheme 3.1, inDMF at 0° C., is added a DMF solution of NaH (about 2 eq.). The reactionmixture is allowed to warm to a temperature of about 25° C. over about 1h. To the resulting mixture is added about 1.2 eq. of an alkyl halide,R₂₀-L, and the reaction mixture allowed to stir until the piperazineCompounds where X is O, Ar₂ is a benzothiazolyl group, and R₂₀ is—(C₁-C₄)alkyl form. The progress of the reaction can be monitored usingconventional analytical techniques including, but not limited to, highpressure liquid chromatography (HPLC), column chromatography, thin-layerchromatography (TLC), column chromatography, gas chromatography, massspectrometry, and nuclear magnetic resonance spectroscopy such as ¹H and¹³C NMR. Piperazine Compounds can be isolated and further treated ifdesired. In one embodiment, the piperazine Compound is isolated byremoving the solvent under reduced pressure. In another embodiment, thepiperazine Compound is isolated by extraction. Piperazine Compounds canbe further treated, for example, by column chromatography orrecrystallization.

5.6.3.2 Methods for Making piperazine Compounds Where X is S and Ar₂ isa Benzothiazolyl Group

Piperazine Compounds where X is S, Ar₂ is a benzothiazolyl group, andR₂₀ is —H can be obtained by the following illustrative method in scheme3.6.

where Ar₁, R₃, R₈, R₉ and m are as defined above.

A compound of formula 46 (about 2 mmol), 1,1′-thiocarbonyldiimidazole(about 2 mmol) (Sigma-Aldrich), and 4-dimethylaminopyridine (DMAP)(Sigma-Aldrich) are suspended in DMSO (about 3 mL) at a temperature ofabout 25° C. and the resulting mixture is heated at about 100° C. forabout 6 h. The reaction mixture is then cooled to a temperature of about25° C. and a compound of formula 43 (about 2 mmol) is added to thereaction mixture and the reaction mixture is heated to about 100° C. forabout 16 h. The reaction mixture is concentrated under reduced pressureto provide piperazine Compounds where X is S, Ar₂ is a benzothiazolylgroup, and R₂₀ is —H. Piperazine Compounds can be chromatographed on asilica column eluted with 5:95 ethyl acetate:hexane.

Piperazine Compounds where X is S, Ar₂ is a benzothiazolyl group, andR₂₀ is —(C₁-C₄)alkyl can be obtained by a method analogous to the methodused to obtain piperazine Compounds where X is O, Ar₂ is abenzothiazolyl group, and R₂₀ is —(C₁-C₄)alkyl as described above inScheme 3.5 except that a piperazine Compound where X is S, Ar₂ is abenzothiazolyl group, and R₂₀ is —H, obtained as described above inScheme 3.6, is used in place of the piperazine Compound where X is O,Ar₂ is a benzothiazolyl group, and R₂₀ is —H.

5.6.3.3 Methods for Making piperazine Compounds Where X is O and Ar₂ isa Benzooxazolyl Group

Piperazine Compounds where X is O, Ar₂ is a benzooxazolyl group, and R₂₀is —H can be obtained by a method analogous to that used to obtain thepiperazine Compounds where X is O, Ar₂ is a benzothiazolyl, and R₂₀ is—H as described in section 5.6.3.1, scheme 3.1, except that a compoundof formula 51, shown below:

where R₈ and R₉ are as defined above, is used in place of the compoundof formula 44.

The compound of formula 51 can be obtained by a method analogous to thatused to obtain the compound of formula 44 as described above in Scheme3.2 except that a compound of formula 52, shown below,

where R₈ and R₉ are as defined above, is used in place of compound 46.

5.6.3.4 Methods for Making piperazine Compounds Where X is S and Ar₂ isa Benzooxazolyl Group

Piperazine Compounds where X is S, Ar₂ is a benzooxazolyl group, and R₂₀is —H can be obtained by a method analogous to that used to obtain thepiperazine Compounds described above in Scheme 3.6 except that acompound of formula 53 is used in place of the compound of formula 44.The compound of Formula 53 can be obtained as described above.

Piperazine Compounds where X is S, Ar₂ is a benzooxazolyl group, and R₂₀is —(C₁-C₄)alkyl can be obtained by a method analogous to the methodused to obtain the piperazine Compounds described above in Scheme 3.5except that a piperazine Compound where X is S, Ar₂ is a benzooxazolylgroup, and R₂₀ is —H, obtained as described above, is used in place ofthe piperazine Compound where X is O, Ar₂ is a benzothiazolyl group, andR₂₀ is —H.

5.6.3.5 Methods for Making piperazine Compounds Where X is O and Ar₂ isa Benzoimidiazolyl Group

Piperazine Compounds where X is O, Ar₂ is a benzoimidiazolyl group, theamide R₂₀ is —H, and the benzoimidiazolyl group R₂₀ is —H can beobtained by a method analogous to that used to obtain the piperazineCompounds described above in Scheme 3.1 except that a compound offormula 54, shown below,

where R₈ and R₉ are as defined above, is used in place of the compoundof formula 44.

The Compound of formula 54 can be obtained by a method analogous to thatused to obtain the compound of formula 44 as described in section5.6.3.1, Scheme 3.2, except that a compound of formula 55, shown below,

where R₈ and R₉ are as defined above, is used in place of the compoundof formula 46. Compounds of formula 55 are commercially available or canbe prepared by procedures known in the art. An illustrative procedurefor obtaining compound 55 is shown below in Scheme 3.7:

where R₈ and R₉ are as defined above.

A compound of formula 56 (about 1 mmol), prepared as described below inScheme 3.11, is dissolved in excess aqueous ammonia in a sealed tube andheated at a temperature of between about 140° C. and 150° C. for about72 h. The mixture is cooled to a temperature of about 25° C. andconcentrated under reduced pressure to provide a residue. In anotherembodiment, the mixture is cooled to a temperature of about 25° C.,extracted with an organic solvent, the organic phase separated from theaqueous phase, and the organic phase is concentrated under reducedpressure to provide a residue. If desired, the residue is then furthertreated to provide the compound of formula 55. In one embodiment, theresidue is recrystallized. In another embodiment, the residue ischromatographed using flash chromatography.

Compounds of formula 56 are commercially available or can be prepared byprocedures known in the art. An illustrative method for preparing thecompound of formula 56 is shown below in scheme 3.8:

where R₈ and R₉ are as defined above.

A compound of formula 57 (about 5 mmol to about 10 mmol) anddi(1H-imidazol-1-yl)methanone (CDI, about 2 eq) is dissolved in THF(about 50 mL to about 70 mL) and the reaction mixture is heated atreflux temperature for about 4 hours. The reaction mixture is thenconcentrated under reduced pressure to provide a residue. Ethyl acetate(about 50 mL) is added to the residue and the resulting insolublematerial is collected by filtration and washed with ethyl acetate toprovide a compound of formula 58. The compound of formula 58 is thenreacted with POCl₃ according to the procedure described in J. Med. Chem.40:586-593 (1997) to provide the compound of formula 56.

The compounds of formula 57 are commercially available or can beprepared by procedures known in the art. An illustrative procedure forobtaining a compound of formula 57 is shown below in scheme 3.9:

where R₈ and R₉ are as defined above.

Aniline hydrochloride 59 (about 12 mmol) is dissolved in concentratedsulfuric acid (about 10 mL) at 0° C. and the resulting solution cooledto a temperature of about −13° C. to about −15° C. About 1 mL of 70%nitric acid is added to the resulting solution over a time period ofabout 30 min. and the reaction mixture allowed to stir for about 2 h ata temperature of from about −13° C. to about −15° C. The reactionmixture is then poured into ice water (about 100 mL), neutralized with5% to 10% aqueous sodium hydroxide, and extracted with about 50 mL ofchloroform. The chloroform layer is separated from the aqueous layer.Concentration under reduced pressure provides a residue that ischromatographed using flash chromatography (silica column and chloroformeluent) to provide a compound of formula 60. The compound of formula 60is dissolved in ethanol (about 50 mL) and hydrogenated for about 12 h ata temperature of about 25° C. using 10% palladium on carbon as acatalyst. The catalyst is removed by filtration and the ethanol isremoved under reduced pressure to provide a residue that ischromatographed using flash chromatography (silica gel eluted with 20:1dichloromethane:methanol) to provide the compound of formula 57. Thecompounds of formula 59 are commercially available or can be prepared byprocedures known in the art.

Piperazine Compounds where X is O, Ar₂ is a benzoimidiazolyl group, theamide R₂₀ is —H, and the benzoimidiazolyl group R₂₀ is —(C₁-C₄)alkyl canbe obtained by a method analogous to that used to obtain the piperazineCompounds where X is O, Ar₂ is a benzoimidiazolyl group, the amide R₂₀is —H, and the benzoimidiazolyl group R₂₀ is —H except that a compoundof formula 61, shown below,

where R₈, R₉, and R₂₀ are as defined above, is used in place of thecompound of formula 54. The compound of formula 61 can be obtained by amethod analogous to that used to obtain the compound of formula 54except that a compound of formula 62, shown below,

where R₈, R₉, and R₂₀ are as defined above, is used in place of thecompound of formula 55. The compound of formula 62 can be obtained asshown below in scheme 3.10.

where R₈, R₉, and R₂₀ are as defined above and L is a halogen.

NaH (about 2 eq) is added to a solution of a compound of formula 55 inDMF at 0° C. and the resulting mixture is allowed to stir and to warm toa temperature of about 25° C. over a period of about one hour. An alkylhalide, R₂₀-L, (about 1 eq.) is then added to the solution and thereaction mixture allowed to stir until a mixture of a compound offormula 62 and a compound of formula 63 is produced. In one embodiment,the alkyl halide is an alkyl iodide. The formation of the compound offormula 62 and the compound of formula 63 can be monitored by analyticalmethods known in the art including, but not limited to, those describedabove. Water is then added to the reaction mixture to produce aprecipitate of the compound of formula 62 and the compound of formula63, which are collected by filtration. The compound of formula 62 andthe compound of formula 63 are then separated to provide the compound offormula 62. The compound of formula 62 and the compound of formula 63can be separated by methods known in the art including, but not limitedto, column chromatography, preparative TLC, preparative HPLC, andpreparative GC.

5.6.3.6 Methods for Making piperazine Compounds Where X is S and Ar₂ isa Benzoimidiazolyl Group

Piperazine Compounds where X is S, Ar₂ is a benzoimidiazolyl group, thethioamide R₂₀ is —H, and the benzoimidiazolyl group R₂₀ is —H can beobtained by a method analogous to that used to obtain the piperazineCompounds described above in scheme 3.6 except that a compound offormula 55 is used in place of the compound of formula 46. The compoundof formula 55 can be obtained as described above.

Piperazine Compounds where X is S, Ar₂ is a benzoimidiazolyl group, thethioamide R₂₀ is —H, and the benzoimidiazolyl group R₂₀ is —(C₁-C₄)alkylcan be obtained by a method analogous to that used to obtain piperazineCompounds as described in section 5.6.3.2, scheme 3.6, except that acompound of formula 62 is used in place of the compound of formula 46.The compound of formula 62 can be obtained as described above.

Piperazine Compounds where X is S, Ar₂ is a benzoimidiazolyl group, thethioamide R₂₀ is —(C₁-C₄)alkyl, and the benzoimidiazolyl group R₂₀ is —Hcan be obtained by a method analogous to that used to obtain thepiperazine Compounds as described above in scheme 3.5 except that apiperazine Compound where X is S and each R₂₀ is —H, prepared asdescribed above, is used in place of the piperazine Compounds where X isO and the amide R₂₀ is —H.

Piperazine Compounds where X is S, Ar₂ is a benzoimidiazolyl group, thethioamide R₂₀ is —(C₁-C₄)alkyl, and the benzoimidiazolyl group R₂₀ is—(C₁-C₄)alkyl can be obtained by a method analogous to that used toobtain the piperazine Compounds where X is O and R₂₀ is —(C₁-C₄)alkyl asdescribed above in scheme 3.5 except that the piperazine Compound whereX is S, the thioamide R₂₀ is —H, and the benzoimidiazolyl group R₂₀ is—(C₁-C₄)alkyl, prepared as described above, is used in place of thepiperazine Compound where X is O and R₂₀ is —H.

Suitable aprotic organic solvents for use in the illustrative methodsinclude, but are not limited to, DCM, DMSO, chloroform, toluene,benzene, acetonitrile, carbon tetrachloride, pentane, hexane, ligroin,and diethyl ether. In one embodiment, the aprotic organic solvent isDCM.

Certain piperazine Compounds can have one or more asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. Apiperazine Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses piperazineCompounds and their uses as described herein in the form of theiroptical isomers, diastereomers, and mixtures thereof, including aracemic mixture.

In addition, one or more hydrogen, carbon or other atoms of a piperazineCompound can be replaced by an isotope of the hydrogen, carbon or otheratoms. Such compounds, which are encompassed by the invention, areuseful as research and diagnostic tools in metabolism pharmacokineticstudies and in binding assays.

5.7 Therapeutic Uses of Compounds of Formula I

In accordance with the invention, the compounds of formula I areadministered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a compound of formula I can beused to treat or prevent any condition treatable or preventable byinhibiting TRPV1. Examples of Conditions that are treatable orpreventable by inhibiting TRPV1 include, but are not limited to, pain,UI, an ulcer, IBD, and IBS.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be used to treat or prevent acute or chronic pain. Examplesof pain treatable or preventable using the compounds of formula Iinclude, but are not limited to, cancer pain, labor pain, myocardialinfarction pain, pancreatic pain, colic pain, post-operative pain,headache pain, muscle pain, arthritic pain, and pain associated with aperiodontal disease, including gingivitis and periodontitis.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can also be used for treating or preventing pain associatedwith inflammation or with an inflammatory disease in an animal. Suchpain can arise where there is an inflammation of the body tissue whichcan be a local inflammatory response and/or a systemic inflammation. Forexample, the compounds of formula I can be used to treat or prevent painassociated with inflammatory diseases including, but not limited to:organ transplant rejection; reoxygenation injury resulting from organtransplantation (see Grupp et al., J. Mol. Cell. Cardiol. 31:297-303(1999)) including, but not limited to, transplantation of the heart,lung, liver, or kidney; chronic inflammatory diseases of the joints,including arthritis, rheumatoid arthritis, osteoarthritis and bonediseases associated with increased bone resorption; inflammatory boweldiseases, such as ileitis, ulcerative colitis, Barrett's syndrome, andCrohn's disease; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory diseases of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory diseases of the skin, includingsclerodermatitis, psoriasis and eczema; inflammatory diseases of thecentral nervous system, including chronic demyelinating diseases of thenervous system, multiple sclerosis, AIDS-related neurodegeneration andAlzheimer s disease, infectious meningitis, encephalomyelitis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosisand viral or autoimmune encephalitis; autoimmune diseases, includingType I and Type II diabetes mellitus; diabetic complications, including,but not limited to, diabetic cataract, glaucoma, retinopathy,nephropathy (such as microaluminuria and progressive diabeticnephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy,gangrene of the feet, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma,foot ulcers, joint problems, and a skin or mucous membrane complication(such as an infection, a shin spot, a candidal infection or necrobiosislipoidica diabeticorum); immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory diseases of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. The compoundsof formula I can also be used for inhibiting, treating, or preventingpain associated with inflammatory disease that can, for example, be asystemic inflammation of the body, exemplified by gram-positive or gramnegative shock, hemorrhagic or anaphylactic shock, or shock induced bycancer chemotherapy in response to pro-inflammatory cytokines, e.g.,shock associated with pro-inflammatory cytokines. Such shock can beinduced, e.g., by a chemotherapeutic agent that is adminstered as atreatment for cancer.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be used to treat or prevent UI. Examples of UI treatable orpreventable using the compounds of formula I include, but are notlimited to, urge incontinence, stress incontinence, overflowincontinence, neurogenic incontinence, and total incontinence.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be used to treat or prevent an ulcer. Examples of ulcerstreatable or preventable using the compounds of formula I include, butare not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer,an esophageal ulcer, or a stress ulcer.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be used to treat or prevent IBD, including Crohn's diseaseand ulcerative colitis.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be used to treat or prevent IBS. Examples of IBS treatableor preventable using the compounds of formula I include, but are notlimited to, spastic-colon-type IBS and constipation-predominant IBS.

Applicants believe that the compounds of formula I, or apharmaceutically acceptable derivative thereof, are antagonists forTRPV1. The invention also relates to methods for inhibiting TRPV1function in a cell comprising contacting a cell capable of expressingTRPV1 with an effective amount of a compound of formula I, or apharmaceutically acceptable derivative thereof. This method can be usedin vitro, for example, as an assay to select cells that express TRPV1and, accordingly, are useful as part of an assay to select compoundsuseful for treating or preventing pain, UI, an ulcer, IBD, or IBS. Themethod is also useful for inhibiting TRPV1 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an effective amount of a compound of formula I, or apharmaceutically acceptable derivative thereof. In one embodiment, themethod is useful for treating or preventing pain in an animal. Inanother embodiment, the method is useful for treating or preventing UIin an animal. In another embodiment, the method is useful for treatingor preventing an ulcer in an animal. In another embodiment, the methodis useful for treating or preventing IBD in an animal. In anotherembodiment, the method is useful for treating or preventing IBS in ananimal.

Examples of tissue comprising cells capable of expressing TRPV1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express TRPV1 are known in theart.

5.8 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, compounds of formula I, or a pharmaceuticallyacceptable derivative thereof, are advantageously useful in veterinaryand human medicine. As described above, compounds of formula I, or apharmaceutically acceptable derivative thereof, are useful for treatingor preventing a Condition.

When administered to an animal, compounds of formula I, or apharmaceutically acceptable derivative thereof, are typicallyadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a compound of formula I, or apharmaceutically acceptable derivative thereof, can be administeredorally. Compounds of formula I, or a pharmaceutically acceptablederivative thereof, can also be administered by any other convenientroute, for example, by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral, rectal, andintestinal mucosa, etc.) and can be administered together with anothertherapeutically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister the compound of formula I, or a pharmaceutically acceptablederivative thereof.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of compounds of formula I, or a pharmaceutically acceptablederivative thereof, into the bloodstream.

In specific embodiments, it can be desirable to administer the compoundsof formula I, or a pharmaceutically acceptable derivative thereof,locally. This can be achieved, for example, and not by way oflimitation, by local infusion during surgery, topical application, e.g.,in conjunction with a wound dressing after surgery, by injection, bymeans of a catheter, by means of a suppository or enema, or by means ofan implant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the compoundsof formula I, or a pharmaceutically acceptable derivative thereof, intothe central nervous system or gastrointestinal tract by any suitableroute, including intraventricular, intrathecal, and epidural injection,and enema. Intraventricular injection can be facilitated by anintraventricular catheter, for example, attached to a reservoir, such asan Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of formula I can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the compounds of formula I, or a pharmaceuticallyacceptable derivative thereof, can be delivered in a vesicle, inparticular a liposome (see Langer, Science 249:1527-1533 (1990) andTreat et al., Liposomes in the Therapy of Infectious Disease and Cancer317-327 and 353-365 (1989)).

In yet another embodiment, the compounds of formula I, or apharmaceutically acceptable derivative thereof, can be delivered in acontrolled-release system or sustained-release system (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled- or sustained-release systemsdiscussed in the review by Langer, Science 249:1527-1533 (1990) can beused. In one embodiment, a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J.Med. 321:574 (1989)). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release (Langer and Wiseeds., 1974); Controlled Drug Bioavailability, Drug Product Design andPerformance (Smolen and Ball eds., 1984); Ranger and Peppas, J.Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)). In yet another embodiment, acontrolled- or sustained-release system can be placed in proximity of atarget of the compounds of formula I, e.g., the spinal column, brain, orgastrointestinal tract, thus requiring only a fraction of the systemicdose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to an animal. Water is a particularlyuseful excipient when the compound of formula I is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or can contain pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, multiparticulates, capsules, capsulescontaining liquids, powders, multiparticulates, sustained-releaseformulations, suppositories, emulsions, aerosols, sprays, suspensions,or any other form suitable for use. In one embodiment, the compositionis in the form of a capsule (see e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed.,19th ed. 1995), incorporated herein by reference.

In one embodiment, the compounds of formula I, or a pharmaceuticallyacceptable derivative thereof, are formulated in accordance with routineprocedures as a composition adapted for oral administration to humanbeings. Compositions for oral delivery can be in the form of tablets,lozenges, aqueous or oily suspensions, granules, powders, emulsions,capsules, syrups, or elixirs, for example. Orally administeredcompositions can contain one or more agents, for example, sweeteningagents such as fructose, aspartame or saccharin; flavoring agents suchas peppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compositions.In these latter platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment, the excipients are ofpharmaceutical grade.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be administered by controlled-release or sustained-releasemeans or by delivery devices that are known to those of ordinary skillin the art. Examples include, but are not limited to, those described inU.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;5,354,556; and 5,733,566, each of which is incorporated herein byreference. Such dosage forms can be used to provide controlled- orsustained-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, ethylcellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled- or sustained-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients of the invention. Theinvention thus encompasses single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gelcaps,and caplets that are adapted for controlled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a compound of formula I to cure or control the condition in aminimum amount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of the compound offormula I, and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can be designed toimmediately release an amount of a compound of formula I, or apharmaceutically acceptable derivative thereof, that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the compound of formula I tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the compound offormula I in the body, the compound of formula I can be released fromthe dosage form at a rate that will replace the amount of compound offormula I being metabolized and excreted from the body. Controlled- orsustained-release of an active ingredient can be stimulated by variousconditions, including but not limited to, changes in pH, changes intemperature, concentration or availability of enzymes, concentration oravailability of water, or other physiological conditions or compounds.

In another embodiment, the compounds of formula I, or a pharmaceuticallyacceptable derivative thereof, can be formulated for intravenousadministration. Typically, compositions for intravenous administrationcomprise sterile isotonic aqueous buffer. Where necessary, thecompositions can also include a solubilizing agent. Compositions forintravenous administration can optionally include a local anaestheticsuch as lignocaine to lessen pain at the site of the injection.Generally, the ingredients are supplied either separately or mixedtogether in unit dosage form, for example, as a dry lyophilized powderor water free concentrate in a hermetically sealed container such as anampoule or sachette indicating the quantity of active agent. Where thecompounds of formula I are to be administered by infusion, they can bedispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the compounds of formula I,or a pharmaceutically acceptable derivative thereof, are administered byinjection, an ampoule of sterile water for injection or saline can beprovided so that the ingredients can be mixed prior to administration.

The amount of the compound of formula I, or a pharmaceuticallyacceptable derivative thereof, that is effective in the treatment orprevention of a Condition can be determined by standard clinicaltechniques. In addition, in vitro or in vivo assays can optionally beemployed to help identify optimal dosage ranges. The precise dose to beemployed will also depend on the route of administration, and theseriousness of the Condition and can be decided according to thejudgment of a practitioner and/or each animal's circumstances. Suitableeffective dosage amounts, however, will typically range from about 0.01mg/kg of body weight to about 2500 mg/kg of body weight, although theyare typically about 100 mg/kg of body weight or less. In one embodiment,the effective dosage amount ranges from about 0.01 mg/kg of body weightto about 100 mg/kg of body weight of a compound of formula I; in anotherembodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of bodyweight; and in another embodiment, about 0.025 mg/kg of body weight toabout 20 mg/kg of body weight.

In one embodiment, an effective dosage amount is administered aboutevery 24 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 12 h until theCondition is abated. In another embodiment, an effective dosage amountis administered about every 8 h until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 h until theCondition is abated.

The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one compound of formula I, or apharmaceutically acceptable derivative thereof, is administered, theeffective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing TRPV1 is contacted with a compound offormula I in vitro, the amount effective for inhibiting the TRPV1receptor function in a cell will typically range from about 0.01 μg/L toabout 5 mg/L; in one embodiment, from about 0.01 μg/L to about 2.5 mg/L;in another embodiment, from about 0.01 μg/L to about 0.5 mg/L; and inanother embodiment, from about 0.01 μg/L to about 0.25 mg/L, of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspensioncomprising the compound of formula I, or a pharmaceutically acceptablederivative thereof, is from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension is about 200 μL.

The compounds of formula I, or a pharmaceutically acceptable derivativethereof, can be assayed in vitro or in vivo for the desired therapeuticor prophylactic activity prior to use in humans. Animal model systemscan be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition in an animalin need thereof can further comprise administering to the animal beingadministered a compound of formula I, or a pharmaceutically acceptablederivative thereof, another therapeutic agent. In one embodiment, theother therapeutic agent is administered in an effective amount.

The present methods for inhibiting TRPV1 function in a cell capable ofexpressing TRPV1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

Effective amounts of the other therapeutic agents are known in the art.However, it is within the skilled artisan's purview to determine theother therapeutic agent's optimal effective-amount range. In oneembodiment of the invention, where another therapeutic agent isadministered to an animal, the effective amount of the compound offormula I is less than its effective amount would be where the othertherapeutic agent is not administered. In this case, without being boundby theory, it is believed that the compounds of formula I and the othertherapeutic agent act synergistically to treat or prevent a Condition.

The other therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroid anti-inflammatory agent,an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca²⁺-channel blocker,an anticancer agent, an agent for treating or preventing UI, an agentfor treating or preventing an ulcer, an agent for treating or preventingIBD, an agent for treating or preventing IBS, an agent for treatingaddictive disorder, an agent for treating Parkinson's disease andparkinsonism, an agent for treating anxiety, an agent for treatingepilepsy, an agent for treating a stroke, an agent for treating aseizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, and mixturesthereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable derivativesthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable derivatives thereof, and mixtures thereof.Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed. 1996) andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed., 19th ed. 1995) which are hereby incorporated by referencein their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

The other therapeutic agent can also be an agent useful for reducing anypotential side effects of a compound of formula I. For example, theother therapeutic agent can be an antiemetic agent. Examples of usefulantiemetic agents include, but are not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sd±1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine;prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlaflaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A compound of formula I, or a pharmaceutically acceptable derivativethereof, and the other therapeutic agent can act additively or, in oneembodiment, synergistically. In one embodiment, a compound of formula Iis administered concurrently with another therapeutic agent; forexample, a composition comprising an effective amount of a compound offormula I and an effective amount of another therapeutic agent can beadministered. Alternatively, a composition comprising an effectiveamount of a compound of formula I and a different composition comprisingan effective amount of another therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a compoundof formula I is administered prior or subsequent to administration of aneffective amount of another therapeutic agent. In this embodiment, thecompound of formula I is administered while the other therapeutic agentexerts its therapeutic effect, or the other therapeutic agent isadministered while the compound of formula I exerts its therapeuticeffect for treating or preventing a Condition.

A composition of the invention is prepared by a method comprisingadmixing a compound of formula I or a pharmaceutically acceptablederivative and a pharmaceutically acceptable carrier or excipient.Admixing can be accomplished using methods known for admixing a compound(or salt) and a pharmaceutically acceptable carrier or excipient. In oneembodiment, the compound of formula I is present in the composition inan effective amount.

5.9 Kits

The invention further encompasses kits that can simplify theadministration of a compound of formula I, or a pharmaceuticallyacceptable derivative thereof, to an animal.

A typical kit of the invention comprises a unit dosage form of acompound of formula I. In one embodiment, the unit dosage form is acontainer, which can be sterile, containing an effective amount of acompound of formula I and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the compound of formula I to treat a Condition.The kit can also further comprise a unit dosage form of anothertherapeutic agent, for example, a second container containing aneffective amount of the other therapeutic agent and a pharmaceuticallyacceptable carrier or excipient. In another embodiment, the kitcomprises a container containing an effective amount of a compound offormula I, an effective amount of another therapeutic agent and apharmaceutically acceptable carrier or excipient. Examples of othertherapeutic agents include, but are not limited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

6. EXAMPLES 6.1 Examples 1-9, 10A and 10B Syntheses of Compounds ofFormula I Example 1 The Syntheses of Compounds Z1, J1, D2, S1, I6, Y1,J6 2,3-Dichloro-5-formylpyridine

To a 500 mL round-bottom flask, manganese oxide (43.5 g, 0.50 mol) wasadded to a solution of 2,3-dichloro-5-hydroxylmethylpyridine (64, 8.10g, 50.0 mmol) in anhydrous CH₂Cl₂ (150 mL). The reaction mixture wasstirred at a temperature of about 25° C. for 48 h, filtered throughCELITE, and concentrated under reduced pressure. The mixture waschromatographed by a silica gel chromatography column eluting with agradient of ethyl acetate (0%-40%)/hexanes to provide 7.2 g of 65 (90%yield). ¹H NMR (400 MHz, CDCl₃) δ 10.08 (1H, s), 8.77 (1H, d, J=1.97Hz), 8.25 (1H, d, J=1.97 Hz). LC/MS (M+1): 176.

2,3-Dichloro-5-vinylpyridine

To a stirred slurry of methyltriphenylphosphonium bromide (10.0 g) intoluene (200 mL) at 0° C. was added potassium t-butoxide (3.07 g)portionwise to produce a yellow slurry. After 1 hr, the reaction mixturewas cooled to −20° C. and 65 (4.0 grams, 22.72 mmol) dissolved intetrahydrofuran (6 mL) was added dropwise to produce a purple coloredslurry. The reaction mixture was heated to 0° C. and stirred foradditional 1 hr. Then the reaction mixture was treated with saturatedaqueous brine (150 mL) and diluted with ethyl acetate (200 mL). Theresulting organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingproduct was chromatographed by silica gel chromatography column elutingwith a gradient of ethyl acetate (0%-10%)/hexanes to provide 2.77 g of66 (70% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (1H, d, J=2.19 Hz), 7.80(1H, d, J=2.19 Hz), 6.63 (1H, dd, J=10.96, 17.80 Hz), 5.86 (1H, d,J=17.80 Hz), 5.45 (1H, d, J=10.96 Hz). LC/MS (M+1): 174.

(S)-1-(5,6-dichloropyridin-3-yl)ethane-1,2-diol and(R)-1-(5,6-dichloropyridin-3-yl)ethane-1,2-diol

To a stirred slurry of AD-mix α (8.95 g) or AD-mix β (8.95 g) in water(32 mL) and t-butanol (27 mL) at 0° C. was added a solution of 66 (0.909g, 5.25 mmol) in t-butanol (5 mL). After 24 hrs, solid sodium sulfite(9.57 g) was added and the resulting slurry was allowed to stir at atemperature of about 25° C. for 30 min. The mixture was extracted threetimes with ethyl acetate (50 mL for each extraction). The organicportions were combined, washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The mixture was chromatographed bya silica gel chromatography column eluting with ethyl acetate(50%-100%)/hexanes to provide 0.75 g of product (67a for AD-mix α or 67bfor AD-mix β) as a white solid (70% yield). ¹H NMR (400 MHz, CDCl₃) δ8.29 (1H, dd, J=0.44, 1.97 Hz), 7.87 (1H, dd, J=0.66, 2.19 Hz), 4.87(1H, m), 3.84 (1H, m), 3.66 (1H, m), 2.83 (1H, d, J=5.92 Hz), 2.11 (1H,t, J=5.92 Hz). LC/MS (M+1): 208.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A 150 mL vessel was charged with 67a (0.70 g, 3.37 mmol),(N-tert-butoxycarbonyl)-1,2,3,6-tetrahrdropyridine-4-boronic acidpinacol ester (68, 1.25 g, 4.04 mmol), Pd(PPh₃)₂Cl₂ (0.189 g, 0.27mmol), potassium carbonate (0.883 g, 6.40 mmol), and a mixture ofDME/EtOH/H₂O (8 mL/4 mL/8 mL). The reaction mixture was purged withnitrogen, the vessel sealed, and the reaction mixture heated at 90° C.with vigorous stirring. After 2 hrs, the reaction mixture was cooled toa temperature of about 25° C. and diluted with EtOAc (50 mL). Theorganic layer was washed with brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was chromatographed by silica gelcolumn chromatography with a gradient of ethyl acetate(50%-100%)/hexanes to provide 0.96 g of 69 (80% yield). ¹H NMR (400 MHz,CD₃OD) δ 8.47 (1H, s), 7.93 (1H, s), 6.06 (1H, m), 4.74 (1H, t, J=5.92Hz), 4.12 (2H, m), 3.67 (4H, m), 2.54 (2H, m), 1.52 (9H, s). LC/MS(M+1): 355.

(S)-1-(3-Chloro-1′,2′,3′,6′-tetrahydro-[2,4]bipyridinyl-5-yl)-ethane-1,2-diol

A vessel (50 mL) was charged with 69 (0.90 g, mmol) and 2M HCl in Et₂O(10 mL) and sealed. The reaction mixture was stirred at 40° C. for 20hrs. The reaction mixture was cooled to a temperature of about 25° C.and the solid precipitated was filtered, washed with Et₂O (20 mL), anddried under reduced pressure to provide 0.65 g of 70 (>99% yield). ¹HNMR (400 MHz, CD₃OD) δ 8.74 (1H, s), 8.52 (1H, s), 6.38 (1H, m), 4.91(1H, m), 4.00 (2H, m), 3.75 (4H, m), 3.54 (2H, t, J=5.92 Hz), 2.89 (2H,m). LC/MS (M+1): 255.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid (4-trifluoromethyl-phenyl)amide

To a suspension of 70 (800 mg, 2.45 mmol) in anhydrous dichloromethane(20 mL), diisopropylethylamine (DIEA, 2 mL) was added dropwise and thereaction mixture was stirred at a temperature of about 25° C. for 10min. The mixture was cooled to −10° C. and1-isocyanato-4-(trifluoromethyl)benzene (462 mg, 2.45 mmol) which wasdiluted with anhydrous dichloromethane (5 mL) was slowly added over 5min. After stirring at −10° C. for 10 additional minutes, the mixturewas chromatographed by a silica gel chromatography column with agradient of methanol (0%-5%)/ethyl acetate to provide 0.60 g of Z1 (56%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (1H, dd, J=0.44, 1.75 Hz), 7.94(1H, dd, J=0.44, 1.75 Hz), 7.72 (4H, m), 6.14 (1H, m), 4.78 (1H, t,J=5.70 Hz), 4.27 (2H, m), 3.82 (2H, t, J=5.70 Hz), 3.70 (2H, m), 2.66(2H, m). MS: m/z=441.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (4-tert-butyl-phenyl)amide

The title compound I1 was obtained using a procedure similar to thatdescribed for obtaining Z1 except that 1-tert-butyl-4-isocyanatobenzenewas used in place of 1-isocyanato-4-(trifluoromethyl)benzene (59%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.48 (1H, dd, J=0.66, 1.97 Hz), 7.94(1H, dd, J=0.66, 1.75 Hz), 7.36 (3H, m), 6.14 (1H, m), 4.79 (1H, t,J=5.26 Hz), 4.27 (2H, m), 3.78 (2H, t, J=5.48 Hz), 3.71 (2H, m), 2.64(2H, m). LC/MS (M+1): 430.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (3-chloro-4-trifluoromethyl-phenyl)amide

To a suspension of 70 (95 mg, 0.29 mmol) in anhydrous dichloromethane (4mL), DIEA (0.5 mL) was added dropwise, and the reaction mixture wasstirred at a temperature of about 25° C. for 10 min. Then the mixturewas cooled to −10° C. and 3-chloro-4-trifluoromethylphenyl)carbamic acid4-nitrophenyl ester (104 mg, 0.29 mmol, prepared in situ from2-chloro-4-nitrobenzotrifluoride (Sigma-Aldrich)) in anhydrousdichloromethane (5 mL) was slowly added over 5 min. After stirring at−10° C. for 10 additional minutes, the mixture was chromatographed by asilica gel chromatography column with a gradient of methanol(0%-5%)/ethyl acetate to provide 30 mg of D2 (23% yield). ¹H NMR (400MHz, CD₃OD) δ 8.50 (1H, m), 7.95 (1H, dd, J=0.44, 1.75 Hz), 7.82 (1H, d,J=1.97 Hz), 7.66 (1H, d, J=8.77 Hz), 7.53 (1H, m), 6.15 (1H, m), 4.78(1H, t, J=5.48 Hz), 4.27 (2H, m), 3.81 (2H, t, J=5.70 Hz), 3.69 (2H, m),2.65 (2H, m). MS: m/z=475.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (3-fluoro-4-trifluoromethyl-phenyl)amide

The title compound S1 was obtained using a procedure similar to thatdescribed for obtaining D2 except that 4-nitrophenyl3-fluoro-4-(trifluoromethyl)phenylcarbamate was used in place of3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (38%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.48 (1H, dd, J=0.44, 1.75 Hz), 7.95(1H, dd, J=0.66, 1.97 Hz), 7.57 (2H, m), 7.36 (1H, m), 6.14 (1H, m),4.77 (1H, t, J=5.48 Hz), 4.23 (2H, m), 3.81 (2H, t, J=5.48 Hz), 3.69(2H, m), 2.65 (2H, m). MS: m/z=459.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (3-ethyl-4-trifluoromethyl-phenyl)amide

The title compound I6 was obtained using a procedure similar to thatdescribed for obtaining D2 except that 4-nitrophenyl3-ethoxy-4-(trifluoromethyl)phenylcarbamate was used in place of3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (25%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.27 (1H, dd, J=0.66, 1.97 Hz), 7.72(1H, dd, J=0.66, 1.97 Hz), 7.25 (2H, m), 6.88 (1H, d, J=8.55 Hz), 5.94(1H, m), 4.57 (1H, t, J=5.48 Hz), 4.08 (2H, m), 3.96 (2H, q, J=7.02 Hz),3.64 (2H, m), 3.52 (2H, m), 2.44 (2H, m), 1.23 (3H, t, J=7.02 Hz). LC/MS(M+1): 486.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (3-chloro-4-trifluoromethoxy-phenyl)amide

The title compound Y₁ was obtained using a procedure similar to thatdescribed for obtaining D2 except that 4-nitrophenyl3-chloro-4-(trifluoromethoxy)phenylcarbamate was used in place of3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (20%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.30 (1H, dd, J=0.44, 1.75 Hz), 7.74(1H, dd, J=0.66, 1.75 Hz), 7.57 (1H, d, J=2.41 Hz), 7.25 (1H, dd,J=2.63, 8.99 Hz), 7.14 (1H, m), 5.94 (1H, m), 4.57 (1H, t, J=5.70 Hz),4.06 (2H, m), 3.59 (2H, t, J=5.70 Hz), 3.50 (2H, m), 2.46 (2H, m). LC/MS(M+1): 492.

(S)-3-Chloro-5-(1,2-dihydroxy-ethyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid (3-ethyl-4-trifluoromethoxy-phenyl)amide

The title compound J6 was obtained using a procedure similar to thatdescribed for obtaining D2 except that 4-nitrophenyl3-ethyl-4-(trifluoromethoxy)phenylcarbamate was used in place of3-chloro-4-trifluoromethylphenyl)carbamic acid 4-nitrophenyl ester (30%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (1H, d, J=1.97 Hz), 7.94 (1H, d,J=1.75 Hz), 7.42 (1H, d, J=2.63 Hz), 7.33 (1H, dd, J=2.85, 8.99 Hz),7.17 (1H, m), 6.16 (1H, m), 4.77 (1H, t, J=5.48 Hz), 4.25 (2H, m), 3.80(2H, t, J=5.48 Hz), 3.70 (2H, m), 2.68 (2H, m), 1.25 (3H, t, J=7.67 Hz).LC/MS (M+1): 486.

Example 2 The Synthesis of Compound N1 2-bromo-3,5-dichloropyridine

A 100 mL round-bottom flask equipped with a condenser was charged with1.82 g of compound 71 (10.0 mmol) and propiononitrile (20 mL), 3.06 gTMSBr (20.0 mmol) was slowly added to the above solution. The reactionmixture was stirred at 100° C. under nitrogen for 14 hrs, then cooled toa temperature of about 25° C. and diluted with EtOAc (100 mL). The EtOAclayer was isolated, dried, and concentrated under reduced pressure toprovide 72 as a yellowish solid (>99% yield).

tert-butyl4-(3,5-dichloropyridin-2-yl)-4-hydroxypiperidine-1-carboxylate

Under nitrogen atmosphere, to a 200 mL diethyl ether solution of 72(2.27 g, 10 mmol) at −78° C. was dropwise added an ice-cold 1.7M t-BuLiin pentane solution (6 mL, 10.5 mmol) via a syringe while maintainingthe mixture below −75° C. After completion of the addition, the reactionmixture was stirred at −78° C. for 2 hrs. Then 20 mL of an anhydrousdiethyl ether solution of 4-BOC-piperridone (1.99 g, 10 mmol) was slowlyadded via a syringe. The reaction mixture was stirred at −78° C. for 2hrs and slowly heated to a temperature of about 25° C. Saturated aqueousNH₄Cl was added to the mixture and the diethyl ether layer was isolated,dried, and concentrated under reduced pressure with a rotary evaporator.Silica gel column chromatography of the residue with ethylacetate/hexanes as eluent provided 2.1 g of 74 as a yellowish oil (61%yield over 2 steps).

tert-butyl 4-(3,5-dichloropyridin-2-yl)-4-fluoropiperidine-1-carboxylate

To a 100 mL DCM solution of 74 (6.0 g, 17.3 mmol) at −78° C. was slowlyadded DAST (2.5 mL, 18.8 mmol) and the resulting mixture was allowed towarm to a temperature of about 25° C. for 16 h, then washed withsaturated NaHCO₃, dried (MgSO₄), and concentrated under reducedpressure. Silica gel column chromatography of the residue withEtOAc/hexanes provided 2.5 g of 75 as yellowish solid (42% yield).

tert-butyl4-(3-chloro-5-vinylpyridin-2-yl)-4-fluoropiperidine-1-carboxylate

To a degassed DMF solution of 75 (0.558 g, 1.6 mmol) in a 100 mL roundbottom flask, was added CsF (0.486 g, 3.2 mmol), di-n-butyl vinylboronic ester (0.388 mL, 1.76 mmol) and Pd(DPPF)₂Cl₂ (0.105 g, 0.128mmol). The reaction mixture was stirred at 100° C. for 14 hr, thencooled to a temperature of about 25° C., diluted with 100 mL ethylacetate, and washed three times with brine (50 mL for each wash). Theorganic layer was isolated, dried, and concentrated under reducedpressure. Silica gel column chromatography of the residue provided 0.33g of 76 as a yellowish oil (60% yield).

(S)-tert-butyl 4-(3-chloro-5-(1,2-dihydroxyethylpyridin-2-yl)-4-fluoropiperidine-1-carboxylate

In a 100 mL round bottom flask, AD-mix-α (0.5 g) was added to a mixtureof t-butanol and water (2 mL/2 mL) and the mixture was stirred at atemperature of about 25° C. for 0.5 hr, then cooled to 0° C. Thissolution was quickly poured into another ice chilled flask whichcontained 76 (140 mg, 0.41 mmol). The mixture was stirred vigorously inan ice bath for 96 h and then diluted with ethyl acetate (50 mL) and 2mL saturated Na₂S₂O₅. The ethyl acetate layer was isolated, dried, andconcentrated under reduced pressure with a rotary evaporator to provide77.

(S)-1-(5-chloro-6-(4-fluoropiperidin-4-yl)pyridin-3-yl)ethane-1,2-diol

A 200 mL round bottom flask was charged with 0.15 g 77 (0.36 mmol)dissolved in about 1 mL dichloromethane. Then 10 mL of 4M HCl in dioxanewas slowly added with vigorous stirring. The flask was sealed with arubber septum and stirred at a temperature of about 25° C. for 16 h. Thereaction mixture was filtered and the solid was washed twice withdiethyl ether (20 mL for each wash) and dried under reduced pressure toprovide 112 mg of 78 as a white solid (>99% yield). MS (M+H): m/z=312.

(S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide

A 100 mL round bottom flask was charged with 90 mg 78 (0.26 mmol)suspended in dichloromethane. DIEA (0.1 mL, 0.72 mmol) and4-trifluoromethyl phenylisocyanate (48 mg, 0.26 mmol) were added, andthe reaction mixture was stirred for 10 minutes. The mixture waschromatographed using a silica flash column with a gradient of 0% to 5%methanol in dichloromethane to provide 50 mg of N1 as a white solid (60%yield). ¹H NMR (CD₃OD) δ 8.49 (d, J=2 Hz, 1H), 7.90 (m, 1H), 7.60 (m,4H), 4.76 (t, J=6 Hz, 1H), 4.17 (m, 2H), 3.68 (m, 2H), 3.45 (m, 2H),2.50-2.34 (m, 4H). MS (M+1): m/z=462.1.

Example 3 Syntheses of Piperazine Compounds K6, L6, M6, V6 and W62,3-dichloro-5-vinylpyridine

To a suspension of methyltriphenylphosphonium bromide (PPh₃CH₃Br, 7.08g, 19.8 mmol, Sigma-Aldrich) in THF (40 mL) at 0° C. was added dropwisea 0.5N solution of potassium bis(trimethylsilyl)amide[K(N(TMS)₂)] intoluene (39.6 mL, 19.8 mmol, Sigma-Aldrich). Then the resultant mixturewas stirred at 0° C. for 1 hour. To the mixture was added a solution of65 (3.17 g, 18.0 mmol) in THF (20 mL) at 0° C. The reaction mixture wasstirred for 2 h at 0° C. The reaction was quenched with water, and themixture was extracted three times with EtOAc (150 mL for eachextraction). The organic portions were combined, washed with brine, andconcentrated to dryness. Compound 66 was obtained as a slight yellowishoil via flash chromatography using ethyl acetate/hexane gradient as aneluent (64% yield). ¹H NMR: (CDCl₃) δ 8.28 (d, J=2.1 Hz, 1H), 7.82 (d,J=2.2 Hz, 1H), 6.65 (dd, J=11.0, 17.5 Hz, 1H), 5.85 (d, J=17.5 Hz, 1H),5.48 (d, J=11.0 Hz, 1H) ppm.

tert-butyl 4-(3-chloro-5-vinylpyridin-2-yl)piperazine-1-carboxylate

To a solution of 66 (1.74 g, 10.0 mmol) in toluene (15 mL) was addedtert-butyl-1-piperiazine-carboxylate (1.86 g, 10.0 mmol, Sigma-Aldrich),palladium acetate (0.113 g, 0.5 mmol, Sigma-Aldrich),1,3-bis(diphenylphosphino)propane (DPPP, 0.220 g, 0.5 mmol,Sigma-Aldrich), and sodium tert-butoxide (1.05 g, 11.0 mmol,Sigma-Aldrich) at a temperature of about 25° C. The reaction mixture wasstirred at 75° C. for 16 h. After cooling to a temperature of about 25°C., water was added to quench the reaction. Then the mixture wasextracted three times with diethyl ether (150 mL for each extraction).The organic portions were combined, washed with brine, and concentratedto dryness. Compound 81 was obtained as a white solid via silica gelcolumn chromatography using an ethyl acetate/hexane gradient as aneluent (88% yield). ¹H NMR: (CDCl₃) δ 8.14 (m, 1H), 7.69 (d, J=1.5 Hz,1H), 6.60 (dd, J=11.0, 17.5 Hz, 1H), 5.68 (d, J=17.5 Hz, 1H), 5.28 (d,J=11.0 Hz, 1H), 3.58 (m, 4H), 3.32 (m, 4H), 1.49 (s, 9H) ppm. MS (M+Na):m/z=346.1.

(S)-tert-butyl 4-(3-chloro-5-(1,2-dihydroxyethylpyridin-2-yl)piperazine-1-carboxylate

To a suspension of 81 (2.84 g, 8.77 mmol) in tert-butanol (60 mL) andwater (60 mL) was added AD-mix-α (11.93 g, 8.77 mmol, Sigma-Aldrich) at0° C. The reaction mixture was stirred at 0° C. for 8 hours thenextracted three times with diethyl ether (150 mL for each extraction).The organic portions were combined, washed with brine, and concentratedto dryness under reduced pressure. Compound 82 was obtained as a whitesolid via flash chromatography using an ethyl acetate/hexane gradient asan eluent (90% yield). ¹H NMR: (CDCl₃) δ 8.14 (d, J=2.0 Hz, 1H), 7.67(d, J=2.2 Hz, 1H), 4.79 (m, 1H), 3.77 (m, 1H), 3.64 (m, 1H), 3.56 (m,4H), 3.28 (m, 4H), 2.87 (d, J=3.2 Hz, 1H), 2.27 (m, 1H), 1.48 (s, 9H)ppm. MS (M+1): m/z=358.1.

(S)-1-(5-chloro-6-(piperazin-1-yl)pyridin-3-yl)ethane-1,2-diol

A suspension of 82 (2.81 g, 7.85 mmol) and 4M HCl in dioxane (60 mL) wasstirred at a temperature of about 25° C. for 1 hour. The reactionmixture was concentrated under reduced pressure to provide 83 as a whitesolid.

(S)—N-(4-tert-butylphenyl)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)piperazine-1-carboxamide

To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was addeddropwise a solution of 4-tert-butylphenyl isocyanate (0.5 mmol,Sigma-Aldrich) in DCM (1.0 mL) at 0° C. The reaction mixture was stirredat a temperature of about 25° C. for 4 hours. Thereafter, silica gelcolumn chromatography using an ethyl acetate/methanol gradient as aneluent provided K6 as a white solid. ¹H NMR: (CD₃OD) δ 8.18 (d, J=2.0Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.30 (m, 4H), 4.66 (t, J=5.5 Hz, 1H),3.68 (m, 4H), 3.62 (m, 2H), 3.34 (m, 4H), 1.30 (s, 9H) ppm. MS (M+1):m/z=433.2.

(S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxamide

To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL), wasadded dropwise a solution of 4-trifluoromethoxyphenyl isocyanate (0.5mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0° C. The reaction mixture wasstirred at a temperature of about 25° C. for 4 hours. Thereafter, silicagel column chromatography using an ethyl acetate/methanol gradient as aneluent provided L6 as a white solid. ¹H NMR: (CD₃OD) δ 8.18 (d, J=1.6Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.47 (m, 2H), 7.18 (m, 2H), 4.66 (t,J=5.9 Hz, 1H), 3.69 (m, 4H), 3.63 (m, 2H), 3.35 (m, 4H) ppm. MS (M+1):m/z=461.1.

(S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide

To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was addeddropwise a solution of 4-trifluoromethylphenyl isocyanate (0.5 mmol,Sigma-Aldrich) in DCM (1.0 mL) at 0° C. The mixture reaction was stirredat a temperature of about 25° C. for 4 hours. Thereafter, direct flashchromatography using an ethyl acetate/methanol gradient as an eluentprovided M6 as a white solid. ¹H NMR: (CD₃OD) δ 8.18 (m, 1H), 7.78 (m,1H), 7.58 (m, 4H), 4.66 (t, J=5.5 Hz, 1H), 3.71 (m, 4H), 3.63 (m, 2H),3.36 (m, 4H) ppm. MS (M+1): m/z=445.0.

N-(6-fluorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide

To a solution of 6-fluorobenzo[d]thiazol-2-amine (122, 336 mg, 2 mmol,Sigma-Aldrich) in DMF (5 mL) was added CDI (123, 357 mg, 2.2 mmol,Sigma-Aldrich) at 0° C. Under vigorous stirring, the reaction mixturewas slowly allowed to warm to a temperature of about 25° C. over 14 h. Awhite precipitate formed. The precipitate was collected by vacuumfiltration, washed twice with EtOAc (10 mL for each wash), and driedunder reduced pressure to provide 124 (yield >99%).

(S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)piperazine-1-carboxamide

To a mixture of 83 (0.3 mmol) in DCM (2.0 mL) and TEA (0.2 mL) was addeddropwise a suspension of 124 (0.3 mmol) in DMF (1.0 mL) at 0° C. Thereaction mixture was stirred at a temperature of about 25° C. for 4hours. Thereafter, direct flash chromatography using an ethylacetate/methanol gradient as an eluent provided V6 as a slightlyyellowish solid. ¹H NMR: (CD₃SOCD₃) δ 8.19 (m, 1H), 7.76 (m, 3H), 7.22(m, 1H), 5.41 (d, J=4.6 Hz, 1H), 4.79 (t, J=6.0 Hz, 1H), 4.53 (m, 1H),3.71 (m, 4H), 3.50 (m, 2H), 3.26 (m, 4H) ppm. MS (M+1): m/z=452.1.

(S)—N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)piperazine-1-carboxamide

To a mixture of 83 (0.5 mmol) in DCM (2.0 mL) and TEA (0.3 mL) was addeddropwise a solution of 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene(0.3 mmol, Sigma-Aldrich) in DCM (1.0 mL) at 0° C. The reaction mixturewas stirred at a temperature of about 25° C. for 4 hours. Thereafter,direct flash chromatography using an ethyl acetate/methanol gradient asan eluent provided W6 as a white solid. ¹H NMR: (CD₃OD) δ 8.18 (m, 1H),7.91 (d, J=2.4 Hz, 1H), 7.78 (d, J=2.6 Hz, 1H), 7.64 (dd, J=2.6, 8.8 Hz,1H), 7.47 (d, J=9.2 Hz, 1H), 4.66 (m, 1H), 3.70 (m, 4H), 3.63 (m, 2H),3.35 (m, 4H) ppm. MS (M+1): m/z=479.1.

Example 4 Synthesis of Compound F45,6-dichloro-N-methoxy-N-methylnicotinamide

To a stirred solution of 5,6-dichloronicotinic acid (87, 7 g, 36.5 mmol)in dichloromethane (100 mL) at a temperature of about 25° C. was addedN,O-dimethylhydroxylamine hydrochloride (3.56 g, 36.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 7.69g, 40.1 mmol), 1-hydroxybenzotriazole (HOBt, 5.42 g, 40.1 mmol), and TEA(7.6 mL, 54.7 mmol). After being stirred for 4.5 h at a temperature ofabout 25° C., the reaction mixture was diluted with ethyl acetate. Themixture was washed with water, 1N aqueous hydrogen chloride, saturatedaqueous sodium hydrogen carbonate and brine, dried (Na₂SO₄), filtered,and concentrated under reduced pressure to provide 88.

1-(5,6-dichloropyridin-3-yl)ethanone

To a stirred solution of 88 in tetrahydrofuran (100 mL) was addeddropwise a 3M solution of methylmagnesium chloride in THF (18 mL, 54.7mmol) at 0° C. under nitrogen. After being stirred for 1 h at 0° C., thereaction mixture was partitioned between ether and saturated aqueousammonium chloride at 0° C. The aqueous layer was extracted with ethylacetate. The organic portions were combined, washed with brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas chromatographed using flash chromatography eluting with a gradientof from 90:10 to 70:30 hexane:ethyl acetate to provide 5.92 g of 89 as awhite solid (85% yield for 2 steps).

2-bromo-1-(5,6-dichloropyridin-3-yl)ethanone

To a stirred solution of 89 (3 g, 15.8 mmol) in glacial acetic acid (25mL) was added dropwise a solution of bromine (0.81 mL, 15.8 mmol) inglacial acetic acid (5 mL) at a temperature of about 25° C. After beingstirred for 24 h at about 25° C., the reaction mixture was precipitated.The precipitate was filtered off and washed with diethyl ether toprovide 3.89 g of 90 as a pale yellow solid (92% yield).

2-(5,6-dichloropyridin-3-yl)-2-oxoethyl acetate

To a stirred solution of 90 (1 g, 3.72 mmol) in DMF (15 mL) at atemperature of about 25° C. was added sodium acetate (457.6 mg, 5.58mmol). The reaction mixture was heated to 70° C. After being stirred for1 h at 70° C., the reaction mixture was cooled to a temperature of about25° C. and diluted with diethyl ether. The mixture was washed withwater, washed with brine, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residue was chromatographed using flashchromatography eluting with a gradient of from 90:10 to 65:35hexane:ethyl acetate to provide 563 mg of 91 as a yellow solid (61%yield).

2-(5,6-dichloropyridin-3-yl)-2,2-difluoroethyl acetate

To a stirred solution of 91 (257 mg, 1.04 mmol) in dichloromethane (10mL) at a temperature of about 25° C. was addedbis(2-methoxyethyl)aminosulfur trifluoride (0.57 mL, 3.11 mmol). Thereaction mixture was heated to 65° C. and stirred for 18 h. Thereafter,the reaction mixture was cooled to a temperature of about 0° C. andpartitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. Theorganic portions were combined, washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waschromatographed using flash chromatography eluting with 90:10hexane:ethyl acetate to provide 201.3 mg of 92 as a yellow oil (75%yield).

tert-butyl4-(3-chloro-5-(1,1-difluoro-2-hydroxyethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To stirred solution of 92 (326.2 mg, 1.41 mmol) indimethoxyethane:ethanol (6 mL, 2:1) at a temperature of about 25° C. wasadded Pd(DPPF)₂Cl₂ (230.3 mg, 0.282 mmol), boron pinacol ester (436.0mg, 1.41 mmol), potassium carbonate (389.8 mg, 2.82 mmol), and water (4mL). The reaction mixture was heated to 70° C. and stirred for 1.5 h.Thereafter, the reaction mixture was cooled to a temperature of about 0°C. and partitioned between ethyl acetate and saturated aqueous ammoniumchloride. The aqueous layer was extracted with ethyl acetate. Theorganic portions were combined, washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waschromatographed using flash chromatography eluting with a gradient offrom 70:30 to 60:40 hexane:ethyl acetate to provide 506.9 mg of 93 asyellow oil (96% yield).

2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)-2,2-difluoroethanolhydrochloride

To a stirred solution of 93 (506.9 mg, 1.35 mmol) in dichloromethane (2mL) at 0° C. was added an excess amount of 4N HCl in dioxane (4 mL).After heating to a temperature of about 25° C. and stirring for 2 h, thereaction mixture was concentrated under reduced pressure. The residuewas crystallized from diethyl ether to provide 292.2 mg of thehydrochloride salt of 94 as a pale yellow solid (70% yield).

4-(3-chloro-5-(1,1-difluoro-2-hydroxyethyl)pyridin-2-yl)-N-(4-(trifluoromethylphenyl)-5,6-dihydropyridine-1(2H)-carboxamide

To a stirred solution of 4-trifluoroaniline (26 mL, 0.289 mmol) indichloromethane (3 mL) at 0° C. was added 4-nitrophenyl chloroformate(58.3 mg, 0.289 mmol) and pyridine (28 mL, 0.347 mmol). After heating toa temperature of about 25° C. and stirring for 2 h, the reaction mixturewas cooled to 0° C. and 94 (90 mg, 0.289 mmol) and DIEA (0.13 mL, 0.723mmol) were added. After 1 h at 0° C., the reaction mixture wasconcentrated under reduced pressure. The residue was chromatographedusing flash chromatography eluting with a gradient of from 70:30 to65:35 hexane:ethyl acetate. The resulting solid was recrystallized fromhexane:ethyl acetate to provide 82.3 mg of F4 as a white solid (62%yield).

Example 5 Synthesis of Compound O42-(tert-butyldimethylsilyloxy)-1-(5,6-dichloropyridin-3-yl)ethanone

To a stirred solution of 67a (19.2 g, 81.4 mmol) in dichloromethane (250mL) at 0° C. under nitrogen was added imidazole (11.1 g, 162 mmol) andtert-butyldimethylsilyl chloride (TBSCl, 12.3 g, 81.4 mmol). Afterheating to a temperature of about 25° C. and stirring for 2.5 h, thereaction mixture was cooled to 0° C. and partitioned between diethylether and saturated aqueous ammonium chloride. The aqueous layer wasextracted with ethyl acetate. The organic portions were combined, washedwith brine, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was chromatographed using flash chromatographyeluting with a gradient of from 90:10 to 80:20 hexane:ethyl acetate toprovide 24.1 g of 97 as pale yellow oil (92% yield).

2-(tert-butyldimethylsilyloxy)-1-(5,6-dichloropyridin-3-yl)ethanone

To a stirred solution of silyl ether 97 (8 g, 24.8 mmol) intetrahydrofuran/methyl sulfoxide (100 mL, 1:1) at a temperature of about25° C. was added o-iodoxybenzoic acid (20.9 g, 74.5 mmol). The reactionmixture was stirred for 5 h at about 25° C. Thereafter, the reactionmixture was cooled to a temperature of about 0° C. and partitionedbetween diethyl ether and saturated aqueous sodium hydrogen carbonate.The aqueous layer was extracted with diethyl ether. The organic portionswere combined, washed with saturated aqueous sodium hydrogen carbonate,washed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was chromatographed using flashchromatography eluting with 90:10 hexane:ethyl acetate to provide 8.0 gof 98 as a yellow oil (99% yield).

5-(3-(tert-butyldimethylsilyloxy)prop-1-en-2-yl)-2,3-dichloropyridine

To a stirred suspension of methyltriphenylphosphonium bromide (11.8 g,33.0 mmol) in toluene (100 mL) at 0° C. under nitrogen was addedpotassium tert-butoxide (3.70 g, 33.0 mmol). After being stirred for 1 hat 0° C., a solution of 98 (8.8 g, 27.5 mmol) in toluene (60 mL) wasadded dropwise to the reaction mixture over 1 h at 0° C. After anadditional 2 h at 0° C., the reaction mixture was partitioned betweendiethyl ether and saturated aqueous ammonium chloride. The aqueous layerwas extracted with diethyl ether. The organic portions were combined,washed with water, washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was chromatographedusing flash chromatography eluting with 90:10 hexane:ethyl acetate toprovide 7.6 g of 99 as a yellow oil (87% yield).

3-(tert-butyldimethylsilyloxy)-2-(5,6-dichloropyridin-3-yl)propan-1-ol

To a stirred solution of 99 (7.6 g, 23.9 mmol) in tetrahydrofuran (120mL) at 0° C. under nitrogen was added borane-methyl sulfide complex (2.3mL, 23.9 mmol). The reaction mixture was heated to a temperature ofabout 25° C. and stirred for 5 h. Thereafter, the reaction mixture wascooled to 0° C. and to the reaction mixture was added 1N sodiumhydroxide (48 mL) dropwise followed by the addition of hydrogen peroxide(17 mL, 35 wt % solution in water). After 2 h more at 0° C., thereaction mixture was partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate. The organic portionswere combined, washed with water, aqueous sodium sulfite and brine,dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Compound 100 was isolated by silica gel column chromatography as ayellow oil (42% yield).

tert-butyl4-(5-(1-(tert-butyldimethylsilyloxy)-3-hydroxypropan-2-yl)-3-chloropyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To stirred solution of 100 (1 g, 2.97 mmol) in dimethoxyethane:ethanol(18 mL, 2:1) at a temperature of about 25° C. was added Pd(DPPF)₂Cl₂(485.6 mg, 0.595 mmol), pinacol ester (919.4 mg, 2.97 mmol), potassiumcarbonate (821.9 mg, 5.95 mmol), and water (12 mL). The reaction mixturewas heated to 60° C. and stirred for 1.5 h. Thereafter, the reactionmixture was cooled to a temperature of about 0° C. and partitionedbetween ethyl acetate and saturated aqueous ammonium chloride. Theaqueous layer was extracted with ethyl acetate. The organic portionswere combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was chromatographedusing flash chromatography eluting with a gradient of from 70:30 to40:60 hexane:ethyl acetate to provide 1.49 g of 101 as a yellow oil(>99% yield).

2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)propane-1,3-diolhydrochloride

To a stirred solution of 101 (1.49 g, 2.97 mmol) in dichloromethane (7mL) and methanol (2 mL) at 25° C. was added excess amount of 4N HCl indioxane (7.5 mL).

After being stirred for 2 h at a temperature of about 25° C., thereaction mixture was concentrated under reduced pressure. The residuewas crystallized from diethyl ether to provide 606.3 mg of thehydrochloride salt of 102 as a pale brown solid (70% yield).

4-(3-chloro-5-(1,3-dihydroxypropan-2-yl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxamide

To a stirred solution of 4-trifluoroaniline (29 mL, 0.328 mmol) indichloromethane (3.5 mL) at 0° C. was added 4-nitrophemyl chloroformate(66.0 mg, 0.328 mmol) and pyridine (32 mL, 0.393 mmol). After heating toa temperature of about 25° C., the reaction mixture was stirred for 2 h.Thereafter, the reaction mixture was cooled to 0° C. and thehydrochloride salt of 102 (100 mg, 0.328 mmol) and DIEA (0.14 mL, 0.819mmol) were added. After 1 h more at 0° C., the reaction mixture waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The organic portions were combined, washedwith saturated aqueous sodium hydrogen carbonate and brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The residuewas chromatographed using flash chromatography eluting with a gradientof from 95:5 to 90:10 chloroform:methanol. The resulting solid wasrecrystallized from isopropyl ether:ethyl acetate to provide 97.2 mg ofO4 as a white solid (65% yield).

Example 6 Determination of the Optical Purity for B1 and N1

The % ee was determined for compounds B1 and N1 as shown below:

¹H NMR and chiral HPLC were used to determine the % ee for both N1 andB1. For the HPLC assay, a CHIRALPAK 1A column was used, the peak areasfor the major and minor enantiomers were determined, and % ee wascalculated from the equation in section 5.3. For ¹H NMR, bis-Mosher'sester derivatives were synthesized for A1, B1, and N1 by a techniqueknown in the art. The % ee determinations were done by adding an excessof Mosher's acid chloride to A1, B1, or N1 (about 0.6 mg) in pyridine-d⁵(0.530 mL) at a temperature of about 25° C. in an NMR tube. A ¹H NMR wastaken 20 h after the addition of Mosher's acid chloride. The peak chosenfor the bis-Mosher's ester of N1 is at approximately δ 6.90, and for B1at δ 6.78. It is important to note the ¹³C satellites were observed at δ(7.02 and 6.78) for N1 and δ (6.90 and 6.65) for B1. The ¹H NMR peaksfor the minor and major enantiomer in each case were integrated, the ¹³Csatellites were subtracted out, and the % ee was calculated.

Example 7 Synthesis of Compound M42,3-dichloro-5-methylsulfonamidylmethyl pyridine

To a suspension of methyl sulfonamide (1.08 g, 11.35 mmol),2,3-dichloropyridinyl aldehyde, (79, 3.0 g, 17.03 mmol), AcOH (1.35 mL),and NaBH(OAc)₃ in dry dichloromethane (70 mL) at 0° C., TEA (3.18 mL,22.7 mmol) was added. The reaction mixture was heated to a temperatureof about 25° C. and stirred for 15 h. Thereafter, saturated NaHCO₃ (2mL) was added. The mixture was extracted twice with ethyl acetate (80 mLfor each extraction). The organic portions were combined, washed twicewith brine (50 mL for each wash), dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The oily residue waschromatographed using a COMBIFLASH apparatus with a 40 g REDISEP columnwith eluent of 40% ethyl acetate in hexanes to provide 2.8 g of 105 (65%yield) and 20% recovered starting material. ¹H NMR (CDCl₃): δ 8.38 (s,1H), 8.27 (s, 1H), 5.03 (bs, NH), 4.35 (d, J=17 Hz, 2H), 3.0 (s, 3H).

tert-butyl4-(3-chloro-5-(methylsulfonamidomethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a suspension of 105 (3.86 g, 15.1 mmol), boronate (4.78, 15.1 mmol),and Pd(PPh₃)₂Cl₂ in ethylene glycol dimethyl ether (38 mL) and EtOH (19mL) at a temperature of about 25° C. was added 2M K₂CO₃ (15 mL). Thereaction mixture was heated 40° C. for 9 hr. Thereafter, the reactionmixture was cooled to a temperature of about 25° C., 1N HCl (10 mL) wasadded. The mixture was extracted twice with ethyl acetate (60 mL foreach extraction). The organic portions were combined, washed with water,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure toprovide the oily residue which was then chromatographed using aCOMBIFLASH apparatus with a 80 g REDISEP column with 30% EtOAc inhexanes to provide 5.0 g of 106 (83% yield). ¹H NMR (CDCl₃): δ 8.35 (s,1H), 7.70 (s, 1H), 6.03 (bs, 1H), 5.34 (bs, t, NH), 4.26 (d, J=6.3 Hz,2H), 4.10 (m, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.89 (s, 3H), 1.42 (s, 9H).

N-((5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)methyl)methanesulfonamide hydrochloride

Compound 106 (1.0 g, 2.5 mmol) was dissolved in dry dichloromethane (10mL) and cooled to 0° C. 4N HCl in dioxane (10 mL, 25 mmol) was added.The reaction mixture was heated a temperature of about 25° C. andstirred for 16 h. The resulting white slurry was filtered and, afterdrying under reduced pressure, 790 mg of the hydrochloride of 107 wascollected as an off-white solid (94% yield).

4-(3-chloro-5-(methylsulfonamidomethyl)pyridin-2-yl-N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxamide

To a suspension of salt (4, 790 mg, 2.34 mmol) in dichloromethane at 0°C. was added DIEA (1.21 mL, 7.03 mmol). The reaction mixture was stirreduntil it became homogenous. α,α,α-trifluoro-p-tolyl isocyanate (0.3 mL,2.22 mmol) was added thereto and the reaction mixture stirred for 10min, until the reaction was complete. The reaction mixture wasconcentrated under reduced pressure. The oily residue waschromatographed using a COMBIFLASH apparatus with a 12 g REDISEP columnwith 50% EtOAc in hexanes to provide 812 mg of M4 as a white solid (71%yield). ¹H NMR (CDCl₃): δ 8.98 (s, 1H), 8.49 (s, 1H), 7.89-7.54 (m, 4H),6.2 (bs, NH), 4.20-4.24 (m, 4H), 3.70 (t, J=5.5 Hz, 2H), 2.96 (s, 3H),2.51-2.33 (bs, 2H).

Example 8 Synthesis of Compound N3

Phenyl 5-(trifluoromethyl)pyridin-2-ylcarbamate

To a stirred solution of 5-(trifluoromethyl)pyridin-2-amine 108 (20 g,123.5 mmol) in dichloromethane (85 mL) at −5° C. was slowly added phenylcarbonochloridate 109 (21.2 g, 136 mmol) over 10 min. At −5° C.,pyridine (11.1 mL, 136 mmol) was then added drop wise to the reactionmixture. After heating the reaction mixture to a temperature of about25° C. and stirring for 1 h, a precipitate gradually formed. Theprecipitate was filtered and washed with dichloromethane and ethylacetate to provide 24.1 g of 110 as a white solid (69.2% yield). ¹H NMR(400 MHz, DMSO-d⁶) δ 11.3 (br s, 1H), 8.75-8.70 (m, 1H), 8.24-8.17 (m,1H), 8.05-7.98 (m, 1H), 7.50-7.40 (m, 2H), 7.33-7.22 (m, 2H).

(R)-1-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)ethane-1,2-diol

The title compound 111 was obtained using a procedure similar to thatdescribed in Example 1 for obtaining 70 except that 67b was used inplace of 67a.

(R)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxamide

To a stirred suspension of the hydrochloride salt of 111 (9.36 g, 32.26mmol) in dichloromethane (30 mL) at −20° C. was added 110 (8.19 g, 29mmol) in one portion. Then at −20° C., DIEA (14 mL, 80.65 mmol) wasadded drop wise to the reaction mixture over 15 min. After being stirredfor 2 h at −20° C., the reaction mixture was diluted with 200 mL ofdichloromethane, washed twice with 1N aqueous sodium hydroxide (200 mLfor each wash), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue (12 g) was dissolved in 25 mL hot ethyl acetateand allowed to cool slowly. The precipitate was collected by vacuumfiltration and washed twice with a solution of 50% ethyl acetate inhexane (100 mL for each wash) to provide 10.15 g of N3 as a white solid(71% yield). ¹H NMR (400 MHz, DMSO-d⁶) δ 9.88 (s, 1H), 8.66-8.60 (m,1H), 8.49-8.44 (m, 1H), 8.10-8.03 (m, 1H), 8.03-7.96 (m, 1H), 7.85-7.81(m, 1H), 6.21-6.14 (m, 1H), 5.57-5.51 (m 1H), 4.89-4.82 (m, 1H),4.64-4.57 (m, 1H), 4.25-4.19 (m, 2H), 3.76-3.67 (m, 2H), 3.60-3.43 (m,2H), 2.62-2.52 (m, 2H).

Example 9 Synthesis of Compounds of Formula I

Using procedures similar to those described above, the followingcompounds of formula I were prepared.

N6: ¹H NMR (CD₃OD) δ 8.41 (s, 1H), 7.59 (m, 5H), 4.80 (t, J=6 Hz, 1H),4.15 (m, 2H), 3.69 (m, 2H), 3.45 (m, 2H), 2.45-2.26 (m, 4H). MS (M+1):m/z=446.1.

O6: ¹H NMR (CD₃OD) δ 8.38 (m, 1H), 7.79 (m, 1H), 7.68 (m, 1H), 7.52 (d,J=8 Hz, 1H), 7.38 (m, 1H), 4.65 (t, J=6 Hz, 1H), 4.04 (m, 2H), 3.57 (m,2H), 3.33 (m, 2H), 2.39-2.21 (m, 4H). MS (M+1): m/z=496.0.

P6: ¹H NMR (CD₃OD) δ 8.55 (m, 1H), 8.41 (s, 1H), 7.98 (m, 2H), 7.67 (m,1H), 4.80 (t, J=6 Hz, 1H), 4.18 (m, 2H), 3.70 (m, 2H), 3.48 (m, 2H),2.46-2.26 (m, 4H). MS (M+1): m/z=447.1.

F1: ¹H NMR (CD₃OD) δ 8.38 (m, 1H), 7.79 (m, 1H), 7.44 (m, 2H), 7.21 (m,1H), 4.65 (t, J=5.6 Hz, 1H), 4.05 (m, 2H), 3.56 (m, 2H), 3.33 (m, 2H),2.38-2.2.21 (m, 4H). MS (M+1): m/z=480.0.

G1: ¹H NMR (CD₃OD) δ 8.43 (m, 1H), 8.37 (d, J=2 Hz, 1H), 7.87 (m, 2H),7.79 (m, 1H), 4.65 (t, J=6 Hz, 1H), 4.08 (m, 2H), 3.57 (m, 2H), 3.35 (m,2H), 2.38-2.22 (m, 4H). MS (M+1): m/z=463.1.

T5: ¹H NMR (CD₃OD) δ 8.64 (dd, J=1.8, 0.6 Hz, 1H), 8.04 (d, J=2.1, 0.3Hz, 1H), 7.59 (dd, J=14.4, 8.9 Hz, 4H), 4.19-4.15 (br d, J=13.8 Hz, 2H),3.78 (dd, J=24.8, 11.3 Hz, 4H), 3.49-3.42 (m, 2H), 2.49-2.34 (m, 4H). MS(M+1): m/z=492.

L1: ¹H NMR (CD₃OD) δ 8.37 (s, 1H), 7.79 (s, 1H), 7.42 (m, 2H), 7.02 (m,1H), 4.64 (t, J=6 Hz, 1H), 4.21 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H),2.35-2.20 (m, 4H). MS (M+1): m/z=469.0.

H1: ¹H NMR (CD₃OD) δ 8.38 (m, 1H), 7.82 (m, 3H), 7.70 (m, 2H), 4.64 (t,J=6 Hz, 1H), 4.06 (m, 2H), 3.57 (m, 2H), 3.36 (m, 2H), 2.40-2.23 (m,4H). MS (M+1): m/z=526.0.

Q3: ¹H NMR (CD₃OD) δ 8.39 (s, 1H), 7.78 (m, 1H), 7.63 (m, 2H), 7.48 (m,1H), 4.78 (t, J=6 Hz, 1H), 4.13 (m, 2H), 3.67 (m, 2H), 3.43 (m, 2H),2.43-2.23 (m, 4H). MS (M+1): m/z=480.5.

Y3: ¹H NMR (CD₃OD) δ 8.41 (m, 1H), 7.67 (m, 1H), 7.55 (m, 2H), 7.34 (m,1H), 4.79 (t, J=6 Hz, 1H), 4.14 (m, 2H), 3.69 (m, 2H), 3.46 (m, 2H),2.43-2.26 (m, 4H). MS (M+1): m/z=464.1.

F5: ¹H NMR (CD₃OD) δ 8.41 (s, 1H), 7.65 (d, J=12 Hz, 1H), 7.53 (m, 2H),7.14 (m, 1H), 4.79 (t, J=6 Hz, 1H), 4.28 (m, 2H), 3.69 (m, 2H), 3.48 (m,2H), 2.45-2.26 (m, 4H). MS (M+1): m/z=453.1.

Q6: ¹H NMR (CD₃OD) δ 8.41 (s, 1H), 7.66 (m, 1H), 7.41 (m, 2H), 7.10 (m,2H), 4.80 (t, J=6 Hz, 1H), 4.08 (m, 2H), 3.69 (m, 2H), 3.50 (m, 2H),2.49-2.23 (m, 4H), 1.33 (s, 9H). MS (M+1): m/z=458.5.

U1: ¹H NMR (MeOD) δ 8.44-8.38 (1H, m), 7.68-7.54 (5H, m), 6.60-6.53 (1H,m), 4.82-4.74 (1H, m), 4.34-4.25 (2H, m), 3.84-3.75 (2H, m), 3.74-3.66(2H, m), 2.82-2.72 (2H, m). MS: m/z=425.

Q1: ¹H NMR (MeOD) δ 8.51-8.46 (1H, m), 7.99-7.92 (3H, m), 7.89-7.82 (2H,m), 6.17-6.12 (1H, m), 4.80-4.73 (1H, m), 4.33-4.25 (2H, m), 3.87-3.76(2H, m), 3.75-3.64 (2H, m), 2.70-2.61 (2H, m). MS: m/z=505.

J1: ¹HNMR (MeOD) δ 8.44-8.37 (1H, m), 7.96-7.89 (1H, m), 7.69-7.51 (3H,m), 7.41-7.34 (1H, m), 6.60-6.53 (1H, m), 4.83-4.75 (1H, m), 4.34-4.26(2H, m), 3.83-3.75 (2H, m), 3.74-3.65 (2H, m), 2.82-2.73 (2H, m). MS:m/z=443.

P1: ¹H NMR (MeOD) δ 8.47-8.37 (1H, m), 8.05-7.83 (5H, m), 7.71-7.59 (1H,m), 6.66-6.53 (1H, m), 4.85-4.74 (1H, m), 4.42-4.28 (2H, m), 3.91-3.64(4H, m), 2.89-2.74 (2H, m). MS: m/z=489.

K1: ¹H NMR (CDCl₃) δ 8.51-8.43 (2H, m), 8.25-8.18 (1H, m), 7.92-7.85(1H, m), 7.83-7.78 (1H, m), 7.53 (1H, br s), 6.22-6.15 (1H, m),4.95-4.84 (1H, m), 4.31-4.19 (2H, m), 3.93-3.64 (4H, m), 3.08-2.97 (1H,m), 2.77-2.63 (2H, m), 2.24-2.14 (1H, m). MS: m/z=442.

R1: ¹H NMR (DMSO) δ 8.50-8.44 (1H, m), 7.87-7.82 (1H, m), 7.82-7.75 (1H,m), 7.70 (1H, br s), 7.26-7.17 (1H, m), 6.23-6.17 (1H, m), 5.58-5.51(1H, m), 4.89-4.82 (1H, m), 4.64-4.57 (1H, m), 4.31-4.21 (2H, m),3.85-3.73 (2H, m), 3.60-3.42 (2H, m), 2.61-2.51 (2H, m). MS: m/z=448.

U3: ¹H NMR (MeOD) δ 8.42-8.36 (1H, m), 7.92 (1H, s), 7.83-7.77 (1H, m),7.67-7.58 (2H, m), 7.55-7.48 (1H, m), 6.58-6.52 (1H, m), 4.80-4.72 (1H,m), 4.31-4.24 (2H, m), 3.81-3.74 (2H, m), 3.72-3.63 (2H, m), 2.80-2.71(2H, m). MS: m/z=459.

L4: ¹H NMR (DMSO) δ 8.45-8.33 (1H, m), 7.85-7.73 (1H, m), 7.69-7.51 (2H,m), 7.29-7.51 (1H, m), 6.63-6.49 (1H, m), 5.62-5.49 (1H, m), 4.91-4.79(1H, m), 4.70-4.56 (1H, m), 4.37-4.23 (2H, m), 3.87-3.71 (2H, m),3.59-3.41 (2H, m), 2.73-2.59 (2H, m). MS: m/z=432.

K4: ¹H NMR (MeOD) δ 8.61-8.49 (1H, m), 8.46-8.34 (1H, m), 8.09-7.87 (2H,m), 7.70-7.56 (1H, m), 6.63-6.51 (1H, m), 4.82-4.72 (1H, m), 4.38-4.26(2H, m), 3.89-3.75 (2H, m), 3.74-3.62 (2H, m), 2.84-2.70 (2H, m). MS:m/z=426.

Example 10 Alternate Synthesis of Compound 67a 5,6-dichloronicotinoylchloride

To a well stirred suspension of 5,6-dichloronicotinic acid 112 (600 g.3.125 mol) and N,N-dimethylformamide (20.0 mL) in dichloroethane (1.2 L)a temperature of about 25° C. was added drop wise with stirring thionylchloride (743.56 g, 6.25 mol). In a reflux apparatus fitted with a gastrap filled with saturated aqueous sodium bicarbonate, the reactionmixture was heated and refluxed, at about to 75° C., until the reactionmixture became a clear solution, after about 3 h. LC/MS analysis of asample quenched in methanol showed only the presence of the methylester. The reaction mixture was cooled to a temperature of about 25° C.and concentrated under reduced pressure to provide 113 as a thickslurry.

1-(5,6-dichloropyridin-3-yl)ethanone

In a dry ice/acetone bath, a suspension of N,O-dimethylhydroxylaminehydrochloride (350.53 g, 3.59 mol) in methylene chloride was cooled to0° C. and TEA (711.5 g, 7.03 mol) was added. Compound 113 was dissolvedin methylene chloride (2.4 L) and added to the mixture at a rate suchthat the reaction mixture temperature did not exceed 15° C. After theaddition of 113 was complete, the reaction mixture was allowed to warmslowly to a temperature of about 25° C. over 16 h. Then the reactionmixture was poured into 2 L of water, the layers were separated, and theaqueous portion was extracted twice with methylene chloride (500 mL foreach extraction). The organic portions were combined, dried (MgSO₄), andconcentrated under reduced pressure to yield a brown solid. The solidwas treated with IL of boiling hexanes and heated at reflux for about 10minutes. The resulting pale orange solution was decanted from the darkyellow-brown tar and allowed to cool. This boiling hexanes treatment wasrepeated twice on the tar (500 mL for each treatment). The hexanemixtures were combined, allowed to cool to a temperature of about 25°C., then cooled in an ice/water bath. The resulting yellow needles werecollected by vacuum filtration and dried in air to provide 730 g of5,6-dichloro-N-methoxy-N-methylnicotinamide 114 (99% yield). ¹H NMR (400MHz, CDCl₃) δ 8.68 (m, 1H), 8.18 (m, 1H), 3.59 (OCH₃, 3H), 3.40, (NCH₃,3H).

431 g of 115 was obtained using a procedure similar to that described inExample 4 for obtaining 89 except that 114 was used in place of 88 (97%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.82 (m, 1H), 8.29 (m, 1H), 2.62(COCH₃, 3H).

1-(5,6-dichloropyridin-3-yl)ethanol

To a well-stirred suspension of 115 (665 g, 3.5 mol) in methanol (3.5 L)at 0° C. was added sodium borohydride (66.21 g, 1.75 mol) portionwise ata rate such that the reaction mixture temperature did not exceed 5° C.After the addition was complete, the reaction mixture was warmed to atemperature of about 25° C. and stirred an additional 1 h. LC/MSanalysis of an aliquot showed that the reaction was essentiallycomplete. The reaction mixture was concentrated under reduced pressure.The residue was mixed with 2 L diethyl ether and 2 L 1N HCl. The layerswere separated and the aqueous layer was extracted twice with diethylether (250 mL for each extraction). The organic portions were combined,dried (MgSO₄), and concentrated under reduced pressure to provide 670 gof 116 as a pale yellow oil (99% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.20(m, 1H), 4.96 (m, 1H), 3.57 (s, 1H), 1.51 (d, J=6.5 Hz, 3H).

2,3-dichloro-5-vinylpyridine

To a solution of 116 (311 g, 1.62 mol) in chlorobenzene (3 L) was addedp-toluene sulfonic acid (431 g, 2.5 mol). The reaction mixture washeated to reflux, about 140° C., and water was removed concurrently. Atthe completion of the reaction, the mixture was concentrated underreduced pressure to about 500 mL, diluted with 2 L of water, andextracted three times with ethyl acetate (1 L for each extraction). Theorganic portions were combined, dried (Na₂SO₄), and concentrated underreduced pressure under mild heating to provide a residue. The residuewas added to 500 mL of methylene chloride and applied to the top ofcolumn packed with 2 kg silica eluted with a 0% to 10% gradient of ethylacetate in hexane to provide 178.55 g of >99% pure2,3-dichloro-5-vinylpyridine 66 as a clear oil, which solidified uponcooling to 4° C. (63% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H),7.85 (m, 1H), 5.72 (m, 1H), 4.88 (m, 1H), 4.37 (m, 1H).

(S)-1-(5,6-dichloropyridin-3-yl)ethane-1,2-diol

In a 5 L three neck round bottom flask fitted with an overheadmechanical stirrer and a thermocouple, a stirred mixture of 66 (150 g,0.861 mol), t-butanol (2.15 L), and water (2.15 L) was cooled with anice/water bath until the temperature of the mixture was below 10° C.AD-mix a (729 g, 1.15 eq.) was added all at once; an endothermic heat ofsolution lowered the temperature of the reaction mixture to 7° C. Thebath was packed with ice and the reaction mixture was allowed to stirfor 16 h while its temperature gradually increased to about 25° C.Thereafter, an aliquot of the reaction mixture was removed, diluted withmethanol, filtered, and analyzed by LC/MS; the LC/MS results showed thatthe reaction was essentially complete.

To promote clumping of the solids and aid filtration, the reactionmixture was diluted with 2 L ethyl acetate and filtered under reducedpressure to remove the solids. The resulting clear mixture was phaseseparated. The aqueous portion was extracted twice with ethyl acetate(250 mL for each extraction). The organic portions were combined, dried(MgSO₄) and concentrated under reduced pressure to provide a dark graysolid. The solid was added to 500 mL of methanol, treated withdecolorizing carbon, boiled, filtered warm through a pad of CELITE, andconcentrated under reduced pressure to provide a gray solid. The solidwas recrystallized from chloroform to provide 115 g of 67a as a whitesolid. A second crop of 67a, 12.3 g, was obtained by concentrating thesupernatant (71% total yield). ¹H NMR (400 MHz, CD₃OD) δ 8.32 (m, 1H),8.0 (m, 1H), 4.75 (t, J=6 Hz, 1H), 3.65 (m, 2H).

Example 10A Synthesis of Compound E6 (5,6-dichloropyridin-3-yl)methylmethanesulfonate

To a solution of (5,6-dichloropyridin-3-yl)methanol (117, 5000 mg, 28.1mmol, Tokyo Chemical Industry Co., Tokyo, Japan) in CH₂Cl₂ (150 mL) at atemperature of about 25° C. was added DIEA (30.9 mmol). The mixture wascooled to 0° C. and methansulfonyl chloride (MsCl, 30.9 mmol) was addeddropwise over 15 min. Thereafter, the reaction mixture was stirred at 0°C. for 1 h. After quenching with water, the mixture was extracted threetimes with CHCl₃/H₂O (100 mL for each extraction), dried (MgSO₄), andconcentrated under reduced pressure to provide a yellow oil. The oil waschromatographed by silica gel column chromatography (Yamazen) with agradient of ethyl acetate (20%-50%)/n-hexane to provide 6360 mg of 118as a yellow oil (88% yield). ¹H NMR (400 MHz, DMSO) δ: 8.51 (1H, s),8.26 (1H, s), 5.35 (2H, s), 3.32 (3H, s).

2-(5,6-dichloropyridin-3-yl)acetonitrile

To a solution of 118 (6360 mg, 24.8 mmol) in ethanol (75 mL) at atemperature of about 25° C. was added a solution of NaCN (32.3 mmol) inwater (25 mL). The reaction mixture was heated to 80° C. and stirred for1 h. After concentration under reduced pressure, the mixture wasextracted three times with EtOAc/H₂O (100 mL for each extraction), dried(Na₂SO₄), and concentrated under reduced pressure to provide an orangeoil. The oil was chromatographed by silica gel column chromatography(Yamazen) with a gradient of ethyl acetate (30%-50%)/n-hexane to provide2648 mg of 119 as a colorless solid (57% yield). ¹H NMR (400 MHz, DMSO)δ: 8.42 (1H, s), 8.18 (1H, s), 4.15 (2H, s).

tert-butyl4-(3-chloro-5-(cyanomethyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a mixture of 119 (187 mg, 1 mmol), 68 (1 mmol), and Na₂CO₃ (1.5 mmol)in 2/1/2 DME/EtOH/H₂O (10 mL) at a temperature of about 25° C. was addedPd(PPh₃)₂Cl₂ (0.1 mmol). The reaction mixture was heated to 120° C. andstirred for 30 min. After cooling to a temperature of about 25° C., themixture was diluted with water, extracted three times with CHCl₃/H₂O (30mL for each extraction), dried (Na₂SO₄), and concentrated under reducedpressure to provide a yellow oil. The oil was chromatographed by silicagel column chromatography (Yamazen) with a gradient of ethyl acetate(20%-50%)/n-hexane to provide 287 mg of 120 as a pale yellow oil (86%yield). ¹H NMR (400 MHz, DMSO) δ: 8.50 (1H, s), 7.95 (1H, s), 6.17 (1H,s), 4.11 (2H, s), 4.02 (2H, s), 3.54 (2H, m), 2.47 (2H, m), 1.43 (9H,s).

2-(5-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)acetonitrile

To a solution of 120 (287 mg, 0.86 mmol) in CH₂Cl₂ (3 mL) at 0° C. wasadded trifluoroacetic acid (TFA, 8.6 mmol). The reaction mixture washeated to a temperature of about 25° C. and stirred for 45 min. Afterconcentration under reduced pressure, the mixture was neutralized with28% aqueous ammonia, extracted three times with CHCl₃/H₂O (50 mL foreach extraction), dried (Na₂SO₄), and concentrated under reducedpressure to provide 200 mg of 121 as a yellow oil (>99% yield). ¹H NMR(400 MHz, DMSO) δ: 8.53 (1H, s), 7.98 (1H, s), 6.12 (1H, s), 4.11 (2H,s), 3.40 (2H, s), 3.19 (1H, br), 2.90 (2H, s), 2.24 (2H, s).

4-(3-chloro-5-(cyanomethyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxamide

To a solution of 121 (200 mg, 0.86 mmol) in CH₂Cl₂ (7 mL) at atemperature of about 25° C. was added1-isocyanato-4-(trifluoromethyl)benzene (0.86 mmol, Acros Organics,Geel, Belgium). The reaction mixture was stirred at a temperature ofabout 25° C. for 1.5 h. After concentration under reduced pressure, themixture was chromatographed by silica gel column chromatography(Yamazen) with a gradient of CHCl₃ (99%-20%)/MeOH to provide 64 mg of E6as a colorless solid (18% yield). ¹H NMR (400 MHz, DMSO) δ: 8.96 (1H,s), 8.52 (1H, s), 7.97 (1H, s), 7.73 (1H, d, J=8 Hz), 7.60 (1H, d, J=8Hz), 6.25 (1H, s), 4.21 (2H, s), 4.12 (2H, s), 3.70 (2H, t, J=8 Hz),2.58 (1H, s), 2.50 (1H, s). LC/MS (100%, tr=6.72 min) [M+H]⁺, m/z=420.8(Calc: 420.1).

Example 10B Synthesis of Compound L1(S)-4-(3-chloro-5-(1,2-dihydroxyethyl)pyridin-2-yl)-4-fluoro-N-(6-fluorobenzo[d]thiazol-2-yl)piperidine-1-carboxamide

A 100 mL round bottom flask was charged with 78 (800 mg, 2.56 mmol)suspended in DMF (2 mL). DIEA (0.87 mL, 5.12 mmol) and 124 (672 mg, 2.56mmol) were added. The resulting reaction mixture was stirred at atemperature of about 25° C. until all the solids dissolved, about 2 h.The reaction mixture diluted with water; an off-white precipitateformed. The precipitate was collected by vacuum filtration. Theprecipitate was washed with water, washed twice with DCM (10 mL for eachwash), and dried under reduced pressure to provide 1.0 g of L1 (yield90%) which was then recrystallized from EtOAc/MeOH. ¹H NMR: δ 8.35 (s,1H), 7.80 (s, 1H), 7.35 (m, 2H), 6.98 (m, 1H), 4.70 (t, 1H), 4.2 (m,2H), 3.6 (m, 2H), 3.3 (m, 2H), 2.25 (m, 4H) ppm. MS (M+1): m/z=468.

6.2 Example 11 In Vivo Assays for Prevention or Treatment of Pain

Test Animals: Each experiment uses rats weighing between 200-260 g atthe start of the experiment. The rats are group-housed and have freeaccess to food and water at all times, except prior to oraladministration of a compound of formula I when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a compound of formula I. The control group is administeredthe carrier for the compound of formula I. The volume of carrieradministered to the control group is the same as the volume of carrierand compound of formula I administered to the test group.

Acute Pain: To assess the actions of the compounds of formula I on thetreatment or prevention of acute pain the rat tail flick test can beused. Rats are gently restrained by hand and the tail exposed to afocused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are as defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a compound of formula I. Data are expressedas tail flick latency(s) and the percentage of the maximal possibleeffect (% MPE), i.e., 20 seconds, is calculated as follows:

${\% \mspace{14mu} {MPE}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)\end{bmatrix}}{\left( {20\mspace{14mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain: To assess the actions of the compounds of formula Ion the treatment or prevention of inflammatory pain the Freund'scomplete adjuvant (“FCA”) model of inflammatory pain is used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical and thermalhyperalgesia and provides reliable prediction of the anti-hyperalgesicaction of clinically useful analgesic drugs (L. Bartho et al.,“Involvement of Capsaicin-sensitive Neurones in Hyperalgesia andEnhanced Opioid Antinociception in Inflammation,” Naunyn-Schmiedeberg'sArchives of Pharmacol. 342:666-670 (1990)). The left hind paw of eachanimal is administered a 50 μL intraplantar injection of 50% FCA. 24hour post injection, the animal is assessed for response to noxiousmechanical stimuli by determining the PWT, or to noxious thermal stimuliby determining the PWL, as described below. Rats are then administered asingle injection of 1, 3, 10 or 30 mg/Kg of either a compound of formulaI; 30 mg/Kg of a control selected from Celebrex, indomethacin ornaproxen; or carrier. Responses to noxious mechanical or thermal stimuliare then determined 1, 3, 5 and 24 hours post administration. Percentagereversal of hyperalgesia for each animal is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}} \times 100}$

Assessments of the actions of the compounds of formula III that weretested revealed these compounds were surprisingly efficacious, e.g.,compounds of formula III significantly reduced FCA-induced thermalhyperalgesia, with ED₅₀ values of from about 0.1 mg/kg to about 10 mg/kgand maximum % reversal values of from about 50% to about 100%. Forexample, for compound D2 the ED₅₀ value for reversal of thermalhyperalgesia was 0.95 mg/kg at 3 hours after administration and 1.63mg/kg at 5 hours after administration of D2. Additionally, the maximum %reversal of thermal hyperalgesia was 78.7% at 5 hours afteradministration of D2.

Neuropathic Pain: To assess the actions of the compounds of formula Ifor the treatment or prevention of neuropathic pain either the Seltzermodel or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction ofanaesthesia, the left thigh of the rat is shaved and the sciatic nerveexposed at high thigh level through a small incision and is carefullycleared of surrounding connective tissues at a site near the trocantherjust distal to the point at which the posterior biceps semitendinosusnerve branches off of the common sciatic nerve. A 7-0 silk suture isinserted into the nerve with a ⅜ curved, reversed-cutting mini-needleand tightly ligated so that the dorsal ⅓ to ½ of the nerve thickness isheld within the ligature. The wound is closed with a single musclesuture (4-0 nylon (Vicryl)) and vetbond tissue glue. Following surgery,the wound area is dusted with antibiotic powder. Sham-treated ratsundergo an identical surgical procedure except that the sciatic nerve isnot manipulated. Following surgery, animals are weighed and placed on awarm pad until they recover from anaesthesia. Animals are then returnedto their home cages until behavioral testing begins. The animal isassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after drug administration for rear paw of theanimal. Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}}\; \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anaesthesia. Animals are then be returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a compound of formulaI for the left rear paw of the animal. The animal can also be assessedfor response to noxious thermal stimuli or for tactile allodynia, asdescribed below. The Chung model for neuropathic pain is described in S.H. Kim, “An Experimental Model for Peripheral Neuropathy Produced bySegmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies (PWL) to a noxious thermal stimulusare determined using a plantar test apparatus (commercially availablefrom Ugo Basile of Italy) following the technique described by K.Hargreaves et al., “A New and Sensitive Method for Measuring ThermalNociception in Cutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). Themaximum exposure time is set at 32 seconds to avoid tissue damage andany directed paw withdrawal from the heat source is taken as the endpoint. Three latencies are determined at each time point and averaged.Only the affected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, Plexiglas compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

Capsaicin-Induced Eye Wipe Test: To assess the effect of compounds offormula I on TRPV1 receptor-mediated pain, the capsaicin-induced eyewipe test is used (N. R. Gavva et al., “AMG 9810[(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide],a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with AntihyperalgesicProperties”, J. Pharmacol. Exp. Ther. 313:474-484 (2005)). The eye wipetest is a reliable high-throughput test of the effect of TRPV1antagonists. Rats are given a single injection of 1, 3, 10 or 30 mg/kgof either a compound of formula I; 30 mg/kg of a control selected fromCelebrex, indomethacin or naproxen; or carrier. At 1, 3 or 5 hours afterdrug administration, 3 μL of a 100 μM capsaicin solution (in 10%EtOH/PBS) is instilled in one eye of each animal with a pipette. Thenumber of forelimb movements (touching or wiping of thecapsaicin-treated eye) are counted during a 2 minute period followinginstillation of capsaicin into the eye.

Assessments of the actions of the compounds of formula III revealedthese compounds were surprisingly efficacious, e.g., compounds offormula III dose-dependently reduced the number of capsaicin-induced eyewipes by from about 25% to about 100% after their administrationrelative to the pre-administration eye wipe value. For example, forcompound N1 the number of eye wipes decreased to 1 to 3 after theadministration of N1 relative to the pre-administration eye wipe valueof 24. Specifically, the eye wipe value was 3 at 1 hour after theadministration of N1 (87.5% decrease), 1 at 3 hours after theadministration (96% decrease), and 2 at 5 hours after the administrationof N1 (92% decrease).

6.3 Example 12 Binding of Compounds of Formula I to TRPV1

Methods for assaying compounds capable of inhibiting TRPV1 are known inthe art, for example, those methods disclosed in U.S. Pat. No. 6,239,267to Duckworth et al.; U.S. Pat. No. 6,406,908 to Mc Intyre et al.; orU.S. Pat. No. 6,335,180 to Julius et al. The results of these assayswill demonstrate that compounds of formula I bind to and modulate theactivity of TRPV1.

Protocol 1

Human TRPV1 Cloning:

Human spinal cord RNA (commercially available from Clontech, Palo Alto,Calif.) is used. Reverse transcription is conducted on 1.0 μg total RNAusing Thermoscript Reverse Transcriptase (commercially available fromInvitrogen, Carlsbad, Calif.) and oligo dT primers as detailed in itsproduct description. Reverse transcription reactions are incubated at55° C. for 1 h, heat-inactivated at 85° C. for 5 min, and RNaseH-treated at 37° C. for 20 min.

Human TRPV1 cDNA sequence is obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences are removed and flanking exonic sequences are joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human TRPV1 are designed as follows: forward primer,GAAGATCTTCGCTGGTTGCACACTGGGCCACA (SEQ ID No: 1); and reverse primer,GAAGATCTTCGGGGACAGTGACGGTTGGATGT (SEQ ID No: 2).

Using these primers, PCR of TRPV1 is performed on one tenth of theReverse transcription reaction mixture using Expand Long TemplatePolymerase and Expand Buffer 2 in a final volume of 50 μL according tothe manufacturer's instructions (Roche Applied Sciences, Indianapolis,Ind.). After denaturation at 94° C. for 2 min PCR amplification isperformed for 25 cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68°C. for 3 min followed by a final incubation at 72° C. for 7 min tocomplete the amplification. The PCR product of about 2.8 kb isgel-isolated using a 1.0% agarose, Tris-Acetate gel containing 1.6 μg/mLof crystal violet and purified with a S.N.A.P. UV-Free Gel PurificationKit (commercially available from Invitrogen). The TRPV1 PCR product iscloned into the pIND/V5-His-TOPO vector (commercially available fromInvitrogen) according to the manufacturer's instructions to result inthe TRPV1-pIND construct. DNA preparations, restriction enzymedigestions, and preliminary DNA sequencing are performed according tostandard protocols. Full-length sequencing confirms the identity of thehuman TRPV1.

Generation of Inducible Cell Lines:

Unless noted otherwise, cell culture reagents are purchased from LifeTechnologies of Rockville, Md. HEK293-EcR cells expressing the ecdysonereceptor (commercially available from Invitrogen) are cultured in GrowthMedium (Dulbecco's Modified Eagles Medium containing 10% fetal bovineserum (commercially available from HYCLONE, Logan, Utah), 1×penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400μg/mL Zeocin (commercially available from Invitrogen)). The TRPV1-pINDconstructs are transfected into the HEK293-EcR cell line using Fugenetransfection reagent (commercially available from Roche AppliedSciences, Basel, Switzerland). After 48 h, cells are transferred toSelection Medium (Growth Medium containing 300 μg/mL G418 (commerciallyavailable from Invitrogen)). Approximately 3 weeks later individualZeocin/G418 resistant colonies are isolated and expanded. To identifyfunctional clones, multiple colonies are plated into 96-well plates andexpression is induced for 48 h using Selection Medium supplemented with5 μM ponasterone A (“PonA”) (commercially available from Invitrogen). Onthe day of assay, cells are loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx is measured using a Fluorescence ImagingPlate Reader (“FLIPR”) as described below. Functional clones arere-assayed, expanded, and cryopreserved.

pH-Based Assay:

Two days prior to performing this assay, cells are seeded onpoly-D-lysine-coated 96-well clear-bottom black plates (commerciallyavailable from Becton-Dickinson) at 75,000 cells/well in growth mediacontaining 5 μM PonA (commercially available from Invitrogen) to induceexpression of TRPV1. On the day of the assay, the plates are washed with0.2 mL 1× Hank's Balanced Salt Solution (commercially available fromLife Technologies) containing 1.6 mM CaCl₂ and 20 mM HEPES, pH 7.4(“wash buffer”), and loaded using 0.1 mL of wash buffer containingFluo-4 (3 μM final concentration, commercially available from MolecularProbes). After 1 h, the cells are washed twice with 0.2 mL wash bufferand resuspended in 0.05 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 3.5 mM CaCl₂and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates are then transferredto a FLIPR for assay. The test compound is diluted in assay buffer, and50 μL of the resultant solution is added to the cell plates and thesolution is monitored for two minutes. The final concentration of thetest compound is adjusted to range from about 50 picoM to about 3 μM.Agonist buffer (wash buffer titrated with 1N HCl to provide a solutionhaving a pH of 5.5 when mixed 1:1 with assay buffer) (0.1 mL) is thenadded to each well, and the plates are incubated for 1 additionalminute. Data are collected over the entire time course and analyzedusing Excel and Graph Pad Prism to determine the IC₅₀.

Capsaicin-Based Assay:

Two days prior to performing this assay, cells are seeded inpoly-D-lysine-coated 96-well clear-bottom black plates (50,000cells/well) in growth media containing 5 μM PonA (commercially availablefrom Invitrogen) to induce expression of TRPV1. On the day of the assay,the plates are washed with 0.2 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 1 mM CaCl₂and 20 mM HEPES, pH 7.4, and cells are loaded using 0.1 mL of washbuffer containing Fluo-4 (3 μM final). After one hour, the cells arewashed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL ofwash buffer. The plates are transferred to a FLIPR for assay. 50 μL oftest compound diluted with assay buffer (1× Hank's Balanced SaltSolution containing 1 mM CaCl₂ and 20 mM HEPES, pH 7.4) are added to thecell plates and incubated for 2 min. The final concentration of thecompound is adjusted to range from about 50 picoM to about 3 μM. HumanTRPV1 is activated by the addition of 50 μL of capsaicin (400 nM), andthe plates are incubated for an additional 3 min. Data is collected overthe entire time course and analyzed using Excel and GraphPad Prism todetermine the IC₅₀.

Protocol 2

For Protocol 2, a Chinese Hamster Ovary cell line (CHO) that has beenengineered to constitutively express human recombinant TRPV1 was used(TRPV1/CHO cells). The TRPV1/CHO cell line was generated as describedbelow.

Human TRPV1 Cloning:

A cDNA for the human TRPV1 receptor (hTRPV1) was amplified by PCR(KOD-Plus DNA polymerase, ToYoBo, Japan) from a human brain cDNA library(BioChain) using primers designed surrounding the complete hTRPV1 openreading frame (forward 5′-GGATCCAGCAAGGATGAAGAAATGG (SEQ ID NO:3), andreverse 5′-TGTCTGCGTGACGTCCTCACTTCT (SEQ ID NO:4)). The resulting PCRproducts were purified from agarose gels using Gel Band Purification Kit(GE Healthcare Bioscience) and were subcloned into pCR-Blunt vector(Invitrogen). The cloned cDNA was fully sequenced using a fluorescentdye-terminator reagent (BigDye Terminator ver3.1 Cycle Sequencing Kit,Applied Biosystems) and ABI Prism 3100 genetic analyzer (AppliedBiosystems). The pCR-Blunt vector containing the hTRPV1 cDNA wassubjected to restriction digestion with EcoR1. The restriction fragmentwas subcloned into expression vector pcDNA3.1 (−) (Invitrogen) and namedpcDNA3.1 (−)-hVR1 plasmid. The sequence of the cDNA encoding TRPV1 isavailable at GenBank accession number AJ277028.

Generation of the TRPV1/CHO Cell Line:

CHO-K¹ cells were maintained in growth medium consisting of α-MEM, 10%FBS (Hyclone), and 100 IU/mL of penicillin—100 μg/mL of streptomycinmixed solution (Nacalai Tesque, Japan) at 37° C. in an environment ofhumidified 95% air and 5% CO₂. The cells were transfected with thepcDNA3.1 (−)-hVR1 plasmid using FuGENE6 (Roche) according to themanufacturer's protocol. 24 hr after transfection, neomycin-resistantcells were selected using 1 mg/mL G418 (Nacalai Tesque). After 2 weeks,individual colonies were picked, expanded, and screened for theexpression of hTRPV1 in the capsaicin-induced Ca²⁺ influx assay (seebelow) with a FLIPR (Molecular Devices). A clone with the largest Ca²⁺response to capsaicin was selected and re-cloned by the same procedure.The cells expressing hTRPV1 were cultured in the growth mediumsupplemented with 1 mg/mL G418. Approximately 1 month later, stableexpression of functional TRPV1 receptors in the selected cell line wasconfirmed by validating Ca²⁺ responses with or without capsazepine(Sigma, at 1 nM-10 μM) in capsaicin assay.

Capsaicin-Induced Ca²⁺ Influx Assay for Cell Selection:

The following assay was performed to identify cells with hTRPV1expression. CHO-K1 cells transfected with pcDNA3.1(−)-hVR1 plasmid wereseeded in 384-well black-wall clear-bottom plates (Corning) andcultivated in growth medium (see above) for 1 day. On the day ofexperiment, culture medium was exchanged to assay buffer (20 mM HEPES,137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose,2.5 mM probenecid, pH 7.4) containing 4 μM Fluo-3-AM (Dojin, Japan).After the incubation at 37° C. for 1 hr, each well was washed 3 timeswith assay buffer using an EMBLA 384 plate washer (Molecular Devices)and refilled with assay buffer. The plates were incubated at atemperature of about 25° C. for 10 min. Subsequently, the plates wereinserted into a FLIPR, and 1.5 μM capsaicin (Sigma) solution prepared inassay buffer was added to each well (final concentration was 500 nM).Cellular responses were monitored for 5 min.

Cell Culture:

1. Cell Culture Media

1. Alpha-MEM (Gibco, CAT: 12561-056, LOT: 1285752): 450 mL.

2. Fetal Bovine Serum (FBS), heat inactivated (Gibco, CAT: 16140-071,LOT: 1276457): 50 mL.3. HEPES Buffer Solution, IM stock (Gibco, CAT: 15630-080): 10 mL (final20 mM).4. Geneticin, 50 mg/mL stock (Gibco, CAT: 10135-035): 10 mL (final 1mg/mL).5. Antimicotic Antibiotic Mixed Solution, 100× stock (Nacalai Tesque,Japan, CAT: 02892-54): 5 mL.

Components 1-5 above were combined at the indicated amounts and storedat 4° C. The cell culture media were brought to about 37° C. before use.Optionally, component 5 can be replaced by penicillin-streptomycinsolution (for example, Gibco 15140-122 or Sigma P-0781).

2. Thawing the Cells

TRPV1/CHO cells were frozen in Cellbanker™ (Juji-Field INC, Japan, CAT:BLC-1) and stored at −80° C. Optimized cryopreservation solutioncontaining dimethyl sulphoxide and FBS was used.

Vials containing the TRPV1/CHO cells were stored at −80° C. Afterremoval from −80° C., the vial was immediately transferred to a 37° C.water bath to thaw for ca. 1-2 minutes. Once completely thawed, thecontents of the vial (1 mL/vial) was transferred to a sterile 15 mL testtube and 9 mL warm culture media were slowly added. The test tube wassubsequently centrifuged at 1000 rpm for 4 min at a temperature of about25° C. The supernatant was removed and the pellet resuspended in 10 mLof culture media. The cell suspension was transferred to a sterile 75cm² plastic flask and incubated at humidified 5% CO₂/95% air at 37° C.To monitor viability, the cells were visually inspected and/or counted,beginning at approximately 1 hr after incubation.

3. Passaging the Cells

The cells in a flask were close to confluence at the time of passaging.Cell culture media were removed from the culture flask and 10 mL ofsterile PBS(−) added and the flask gently shaken. The PBS was removedfrom the flask and 2 mL of trypsin/EDTA solution (0.05% trypsin withEDTA-4Na; Gibco, CAT: 25300-054) was added and the flask gently shaken.The flask was incubated at 37° C. for about 2 min. 8 mL cell culturemedia were subsequently added to the flask and the flask shaken toensure that all cells were in solution. The cell suspension was thentransferred to a sterile 15 mL or 50 mL plastic tube, centrifuged at1,000 rpm for 4 min at a temperature of about 25° C. The supernatant wasremoved and the pellet resuspended in ca. 5 mL of culture media. Thecell count was measured using the Burker-Turk hemocytometer.

The cells were seeded into a sterile 75 cm² plastic flask in ca. 0.8×10⁵cells/mL for 72 hr and incubated in humidified 5% CO₂/95% air at 37° C.

4. Freezing the Cells

The procedure up to the measurement of the cell count was the same as inthe section Passaging the Cells above. Subsequently, the cell suspensionwas centrifuged at 1,000 rpm for 4 min at a temperature of about 25° C.The supernatant was removed and the pellet resuspended in Cellbanker™solution to get a final concentration of from 5×10⁵ to 5×10⁶ cells/mL.The cell suspension was transferred into appropriately labeled 1 mLcryovials and then placed into the −80° C. freezer.

pH-Based Assay:

The following assay was conducted to determine the concentration ofsulfuric acid that would give rise to a pH that induces a Ca²⁺ responseoptimal to test compounds for their effect on TRPV1.

1. Cells

TRPV1/CHO cells were seeded in the 96-well clear-bottom black-wall plate(Nunc) at densities of 1-2×10⁴ cells/well and grown in 100 μL of culturemedium (alpha-MEM supplemented with 10% FBS, 20 mM HEPES, 1 mg/mLgeneticin and 1% antibiotic-antimycotic mixed stock solution) for 1-2days before the experiment.

2. Determination of pH Sensitivity and Agonist Dose

2.1. Agonist Solution

Different agonist solutions with sulfuric acid concentrations of from 15mM to 18 mM (see FIG. 1) were prepared by diluting 1M sulfuric acid withmeasuring buffer. The different sulfuric acid concentrations in theagonist solutions were selected such that a 1:4 dilution would result ina final sulfuric acid concentration of between 3.0 mM to 3.6 mM,respectively, as indicated in FIG. 1.

2.2. Assay

pH dependent Ca²⁺ responses in TRPV1/CHO cells cultured in a 96-wellplate are shown in FIG. 2. In particular, Ca²⁺ influx into TRPV1/CHOcells in response to low pH as measured by Fura-2 AM fluorescence isindicated in FIG. 2. The cells were stimulated using 3.0 mM (well numberB1-6), 3.1 mM (C₁₋₆), 3.2 mM (D1-6), 3.3 mM (E1-6), 3.4 mM (F1-6), 3.5mM (G1-6), or 3.6 mM (H1-6) H₂SO₄ or pH 7.2 measuring buffer withoutH₂SO₄ (A1-6) (FIG. 2).

(1) Culture medium was removed using an 8-channel-pipette (Rainin, USA)from the 96-well plate and the wells were refilled with 100 μL ofloading buffer (20 mM HEPES, 115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂, 1.8mM CaCl₂, 13.8 mM D-glucose, 2.5 mM probenecid, pH 7.4) containing 5 μMFura-2 AM (Dojin, Japan).

(2) The 96-well plate was incubated at 37° C. for 45 min.

(3) The loading buffer was removed from each well. The cells weresubsequently washed twice with 150 μL of measuring buffer (20 mM HEPES,115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂, 5.0 mM CaCl₂, 13.8 mM D-glucose,0.1% BSA, pH 7.4) (no probenecid). The wells were then refilled with 80μL of measuring buffer.

(4) After an incubation at 4° C. for 15 min, the 96-well plate wastransferred to FDSS-3000 (Hamamatsu Photonics, Japan).

(5) The Fura-2 fluorescent intensity was monitored at a wavelength of340 nm and at 380 nm, respectively, at a rate of 0.5 Hz for a total of240 seconds. After 16 time points (32 sec) of baseline detection, 20 μLof agonist solution was added to each well. The final volume was 100μL/well.

(6) Fluorescence intensity ratio refers to the fluorescence intensity at340 nm over the fluorescence intensity at 380 nm at a particular timepoint. The baseline was set as the average of the fluorescent intensityratios for the first 16 time points before the addition of agonistsolution. The maximum response was the highest fluorescent intensityratio during the 60 time points following addition of agonist solution.

(7) Maximal signal ratios from each well were calculated as output datausing the FDSS-3000 analysis program. Data were analyzed using Excel(Microsoft) and XLfit (idbs) software.

2.3. pH Determination

After the observation of Ca²⁺ responses, the buffer of each lane (50μL/well, 8-20 wells/plate) was collected well by well and the pH valueswere measured using a portable pH meter (Shindengen, Japan).

As shown in FIG. 2, the Ca²⁺ responses in lanes D and E wereintermediate and therefore optimal for testing the effects of compoundson the TRPV1 calcium channel. The final sulfuric acid concentrations inthe wells of these lanes were 3.2 mM and 3.3 mM, respectively. Thesefinal sulfuric acid concentrations were obtained using agonist solutionswith 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively(lanes D and E in FIG. 1). The pH obtained using these sulfuric acidconcentrations was ca. 5.0-5.1.

Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acidconcentrations, respectively, (lanes D and E in FIG. 1) were selectedfor the experiments described below in section 3.

3. pH Assay

3.1. Agonist

Two different agonist solutions with different H₂SO₄ concentrations wereused for the pH assay (FIG. 3A). For one half of a 96-well plate oneagonist solution was used, for the other half the other agonistsolution. The agonist solutions were obtained by diluting sulfuric acid(H₂SO₄, 1M) with measuring buffer. The concentrations for the twoagonist solutions were determined as described above in Section 2 ofProtocol 2.

The sulfuric acid concentrations between the two agonist solutionsdiffered by 0.5 mM. In the experiment described in Section 2 of Protocol2, the sulfuric acid concentrations in the agonist solutions weredetermined to be 16 mM and 16.5 mM, respectively. After 1:4 dilution ofthe agonist solutions, the final sulfuric acid concentration was 3.2 mMand 3.3 mM, respectively. The resulting pH value for the pH assay was5.0 to 5.1.

3.2. Test Compounds

Test compounds were dissolved in DMSO to yield 1 mM stock solutions. Thestock solutions were further diluted using DMSO in 1:3 serial dilutionsteps with 6 points (1000 μM, 250 μM, 62.5 μM, 15.625 μM, 3.9062 μM and0.977 μM). The thereby-obtained solutions were further diluted inmeasuring buffer (1:100) as 10× stock serial dilutions with a DMSOconcentration of 1%. 10 μL of a 10× stock was added into each well atstep 3.3.(4) of Protocol 2. Thus, the final concentrations ofantagonists ranged from 1000-0.977 nM containing 0.1% DMSO (FIG. 3B).

3.3. Assay

Steps (1) and (2) of this Assay were the same as steps 2.2.(1) and2.2.(2) of Protocol 2, respectively.

(3) The cells were washed twice with 150 μL of measuring buffer(mentioned in 2.2.(3) of Protocol 2, no probenecid). The wells weresubsequently refilled with 70 μL of measuring buffer.

(4) Either 10 μL of measuring buffer or 10 μL of 10× stock serialdilution of test compound (described in 3.2. above) were applied to eachwell. Usually, only one test compound was tested per 96-well plate. Thenumber of replicates per 96-well plate for a particular antagonist at aparticular concentration was 7×2 since two different sulfuric acidconcentrations were used per 96-well plate (N=7×2) (FIG. 3).

Step (5) was the same as 2.2.(4) above.

(6) Fura-2 fluorescent intensity was monitored as described in 2.2.(5)above. After 16 time points of baseline detection, 20 μL of agonistsolution (measuring buffer titrated with H₂SO₄ to yield pH 5.0-5.1 whenmixed 1:4 with the measuring buffer containing test compound) was addedto each well (final volume 100 μL/well).

Steps (7) and (8) were as described in 2.2.(6) and 2.2.(7) above,respectively.

3.4. pH check

(1) The pH values of the buffer in the wells of A1→H1 and A7→H7(longitudinally; FIG. 3) were measured one by one using a portable pHmeter.

(2) When a well was confirmed as pH 5.0 or 5.1, the next five wells toits right were checked one after another.

(3) For IC₅₀ calculation, only the data from wells with pH values of5.0-5.1 were used.

The number of wells tested for their pH varied among plates (about 16-60wells/plate). The number depended on the results of 3.4.(1) above andthe Ca²⁺ responses.

Capsaicin-Based Assay:

One day prior to assay, TRPV1/CHO cells were seeded in 96-wellclear-bottom black plates (20,000 cells/well) in growth media. On theday of the experiment, the cells were washed with 0.2 mL 1× Hank'sBalanced Salt Solution (Life Technologies) containing 1.6 mM CaCl₂ and20 mM HEPES, pH 7.4 (“wash buffer”). Subsequently, the cells were loadedby incubation in 0.1 mL of wash buffer containing Fluo-4 at 3 μM finalconcentration. After 1 hour, the cells were washed twice with 0.2 mLwash buffer and resuspended in 0.1 mL wash buffer. The plates were thentransferred to a Fluorescence Imaging Plate Reader (Molecular Devices).Fluorescence intensity was monitored for 15 seconds to establish abaseline. Subsequently, test compounds diluted in assay buffer (1×Hank's Balanced Salt Solution containing 1 mM CaCl₂ and 20 mM HEPES, pH7.4) containing 1% DMSO were added to the cell plate and fluorescencewas monitored for 2 minutes. The final concentration of the compound wasadjusted to range from 100 μM to 1.5625 μM. If the test compound was anespecially potent antagonist, the final concentration of the compoundwas adjusted to range from 10 μM to 1.5625 nM. Human TRPV1 was thenactivated by the addition of 50 μL capsaicin (100 nM finalconcentration) and plates incubated for an additional 3 min. Data werecollected over the entire time course and analyzed using Excel and thecurve-fitting formula GraphPad Prism.

The results of the assays of Protocol 2 are shown in Table I, whichdemonstrates that many compounds of formula I have superior potency. TheIC₅₀ data provided in Table I are shown as mean±standard error of themean; the number of trials conducted for each assay is shown inparentheses except for only a single trial where no number of trials isshown in parentheses. No standard error of the mean is determined whenthe number of trials is less than 3.

TABLE I TRPV1 IC₅₀ Potency Human Capsaicin CHO Human pH CHO Compound(hCAP-CHO) (nM) (hpH-CHO) (nM) Structure A1 7.0 ± 1.8 (4)

B1 7.81 ± 1.2 (4) 7.40 ± 0.3 (3)

C1 15.3 ± 6.9 (3) 11.3 ± 0.8 (3)

D1 16.5 ± 4.1 (3) 0.9 (2)

E1 18.5 ± 4.9 (3)

F1 18.6 ± 6.8 (3) 9.0 ± 2.3 (3)

G1 31.3 ± 8.8 (3) 16.4 (2)

H1 31.7 ± 8.9 (3)

I1 33.8 ± 9.1 (3) 1.1 ± 0.2 (3)

J1 34.5 ± 17.5 (3) 18.0 (2)

K1 35.1 ± 8.8 (3) 39.5 (2)

L1 35.3 ± 12.0 (3) 27.5 ± 3.4 (4)

M1 37.5 ± 9.0 (3) 5.7 ± 0.3 (5)

N1 38.7 ± 5.3 (3) 6.3 ± 0.8 (5)

O1 41.1 ± 17.8 (3)

P1 50.5 ± 9.5 (3)

Q1 51.0 ± 16.4 (3) 8.1 ± 0.7 (3)

R1 51.0 ± 18.8 (3)

S1 53.5 ± 16.3 (3) 16.3 ± 2.0 (3)

T1 60.3 ± 19.0 (3) 29.7 ± 2.3 (3)

U1 61.3 ± 22.5 (3) 14.7 ± 3.3 (3)

V1 66.3 ± 5.7 (3) 22.4 ± 1.1 (3)

W1 68.9 ± 18.4 (3) 9.3 ± 1.9 (3)

X1 74.4 ± 11.5 (3) 18.8 ± 1.6 (6)

Y1 74.7 ± 18.4 (4) 13.5 ± 1.2 (3)

Z1 75.8 ± 12.4 (4) 11.6 ± 0.7 (3)

A2 84.1 ± 11.2 (3)

B2 77.6 ± 12.0 (4) 40.5 (2)

C2 98.7 ± 33.9 (5) 41.8 ± 3.8 (3)

D2 85.3 ± 20.7 (6) 10.8 ± 0.9 (3)

E2 107.4 ± 18.8 (5) 20.3 ± 1.7 (4)

F2 108.0 ± 24.3 (3) 62.9 ± 8.8 (4)

G2 112.4 ± 22.3 (3) 84.8 ± 8.8 (3)

H2 118.1 ± 22.1 (3) 13.1 ± 2.1 (3)

I2 122.0 ± 7.1 (3) 18.0 ± 1.0 (5)

J2 128.6 ± 26.0 (3) 41.7 ± 4.4 (3)

K2 140.8 ± 41.9 (3) 47.2 ± 6.7 (3)

L2 153.0 ± 24.4 (3) 57.4 ± 9.1 (5)

M2 156.3 ± 5.6 (3) 42.0 ± 9.1 (3)

N2 161.4 ± 16.6 (3) 27.3 ± 2.6 (6)

O2 161.8 ± 29.5 (3) 18.8 ± 4.0 (4)

P2 172.9 ± 40.3 (4) 44.4 (2)

Q2 194.4 ± 27.1 (3) 85.9 ± 21.8 (4)

R2 199.9 ± 26.8 (3) 49.6 ± 3.4 (5)

S2 205.3 ± 35.4 (3) 31.9 ± 2.5 (3)

T2 225.8 ± 69.3 (5)

U2 230.5 ± 45.3 (4) 53.4 ± 5.9 (3)

V2 234.2 ± 44.6 (3) 83.2 ± 7.6 (3)

W2 244.8 ± 34.4 (3) 241.3 ± 34.9 (5)

X2 248.4 ± 25.1 (3) 81.1 ± 10.5 (3)

Y2 350.9 ± 69.8 (3) 59.9 ± 11.8 (3)

Z2 401.0 ± 122.4 (3) 247.6 ± 45.3 (3)

A3 414.1 ± 99.6 (3) 309.5 ± 38.9 (3)

B3 537.2 ± 62.0 (3) 106.0 ± 11.4 (5)

C3 541.4 ± 215.8 (3)

D3 564.8 ± 58.6 (3) 39.8 ± 2.2 (3)

E3 670.7 ± 133.1 (3) 141.0 ± 23.1 (3)

F3 915.7 ± 305.6 (4) 584.8 (2)

G3 1075.9 ± 201.8 (3)

H3 1114.9 ± 134.0 (3)

I3 1363.7 ± 337.4 (3)

J3 2940.7 ± 318.9 (3)

K3 >10,000 (3)

L3 37.1 ± 14.8 (3) 38.3 ± 4.0 (3)

M3 186.9 ± 43.7 (3) 30.0 ± 2.1 (3)

N3 161.1 ± 41.7 (3) 223.3 ± 14.0 (3)

O3 46.0 ± 11.3 (3)

P3 183.4 ± 38.1 (3) 28.5 (2)

Q3 14.3 ± 1.3 (3) 5.3 ± 1.0 (4)

R3 15.5 ± 3.5 (3)

S3 17.7 ± 2.0 (3) 9.2 (3)

T3 23.8 ± 6.8 (3) 12.9 (3)

U3 27.9 ± 9.9 (3) 13.5 (2)

V3 34.0 ± 9.2 (3)

W3 35.6 ± 8.9 (3) 22.4 (2)

Y3 43.9 ± 10.0 (3)

A4 55.1 ± 8.6 (4)

B4 57.2 ± 11.6 (3) 5.8 ± 1.3 (4)

C4 66.2 ± 7.5 (3) 18.6 ± 2.8 (3)

D4 69.6 ± 6.9 (3) 54.8 (2)

E4 75.7 ± 12.8 (3)

F4 86.7 ± 18.9 (3) 32.5 ± 2.4 (3)

H4 175.8 ± 28.4 (3) 97.0 ± 9.9 (3)

K4 210.2 ± 19.5 (3)

L4 439.4 ± 139.8 (3)

M4 471.3 ± 127.3 (3)

N4 1312.9 ± 220.5 (3)

O4 1517.2 ± 338.6 (3)

P4 1809.9 ± 302.1 (4)

Q4 2897.7 ± 302.1 (3)

R4 3278.6 ± 760.6 (3)

S4 7028.4 ± 2059.0 (3)

X4 38.4 ± 8.0 (3)

Z4 62.8 ± 11.4 (3) 16.5 ± 3.3 (3)

B5 106.5 ± 21.0 (3) 15.0 ± 3.0 (3)

C5 107.7 ± 38.4 (3) 39.9 ± 7.9 (3)

D5 132.7 ± 29.1 (3)

E5 132.8 ± 28.5 (3) 33.8 (2)

F5 166.1 ± 24.7 (3)

G5 400.0 ± 10.6 (3) 108.5 (2)

H5 520.0 ± 88.6 (3) 515.6 ± 99.2 (3)

I5 709.1 ± 94.1 (3) 117.6 ± 27.5 (3)

T4 1330.7 ± 334.3 (3) 1175.1 ± 147.2 (3)

J5 1879.8 ± 633.8 (3)

K5 2753.2 ± 541.9 (3)

L5 >10,000 (3)

M5 >25,000 (2)

N5 140.25 (2)

O5 243.62 (2)

P5 49.51 (2)

R5 346.05 (2)

T5 451.5 ± 92.4 (3)

U5 19.9 ± 6.9 (3)

V5 45.5 ± 2.1 (3) 10.1 ± 1.4 (6)

W5 423.2 ± 122.5 (3) 71.2 ± 10.5 (5)

X5 229.8 ± 65.5 (3)

Y5 196.4 ± 37.7 (3) 108.5 ± 7.7 (3)

Z5 35.5 ± 3.9 (3) 16.4 ± 1.9 (5)

A6 49.8 ± 12.1 (3) 9.0 ± 0.8 (4)

B6 922.2 ± 204.6 (3) 361.6 ± 69.1 (3)

C6 >25,000 (2)

D6 620.5 ± 116.5 (3)

E6 265 165

F6 864 467

G6 >25,000

H6 924

K6 9.8 ± 2.3 (4) 0.8 ± 0.1 (3)

L6 14.2 ± 1.4 (3) 5.8 (2)

M6 7.0 ± 1.0 (5) 3.5 ± 1.0 (3)

V6 16.0 ± 1.6 (3) 6.2 (2)

W6 32.9 ± 11.8 (3) 14.9 ± 2.2 (4)

200 136 31.8

201 131 185

202 182 590

203 90.2 51.2

204 167 154

205 >25,000

206 508 1463

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples which are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A compound of formula IA:

or a pharmaceutically acceptable derivative thereof, wherein X is O, S,N—CN, N—OH, or N—OR₁₀; W is N or C; the dashed line denotes the presenceor absence of a bond, and when the dashed line denotes the presence of abond or W is N then R₄ is absent, otherwise R₄ is —H, —OH, —OCF₃, -halo,—(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl, —CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃,—OR₁₀, —SR₁₀, —COOH, —COOR₁₀, —C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀,—NHC(O)R₁₃, —CON(R₁₃)₂, —S(O)₂R₁₀, or —NO₂; R₁₀ is —(C₁-C₄)alkyl; eachR₁₃ is independently —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl; Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2; Y₁, Y₂, and Y₃ are independently C, N, orO; wherein no more than one of Y₁, Y₂, or Y₃ can be O, and for each Y₁,Y₂, and Y₃ that is N, the N is bonded to one R₂₁ group, and for each Y₁,Y₂, and Y₃ that is C, the C is bonded to two R₂₀ groups, provided thatthere are no more than a total of two (C₁-C₆)alkyl groups substituted onall of Y₁, Y₂, and Y₃; R_(12a) and R_(12b) are independently —H or—(C₁-C₆)alkyl; E is ═O, ═S, ═CH(C₁-C₅)alkyl, ═CH(C₁-C₅)alkenyl,—NH(C₁-C₆)alkyl, or ═N—OR₂₀; R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN,—OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —OC(halo)₃,—OCH(halo)₂, or —OCH₂(halo); each R₂ is independently: (a) -halo, —OH,—O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, or -phenyl, or (b) a group of formula Q; wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo; Z₂ is—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CH₂—OR₇, -phenyl,or -halo; each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl; Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or—N(R₂₀)₂; J is —OR₂₀, —SR₂₀, —N(R₂₀)₂, or —CN; provided that at leastone R₂ group is a group of formula Q, and provided that when Z₁ is —OR₇or —SR₇, then Z₂ is not -halo; each R₃ is independently: (a) —H,—(C₁-C₆)alkyl, or —CH₂OR₇; or (b) two R₃ groups together form a(C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups, and which bridge optionally contains—HC═CH— within the (C₂-C₆)bridge; or (c) two R₃ groups together form a—CH₂—N(R_(a))—CH₂— bridge, a

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c); R_(b) is: (a)—H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to 7-membered)heterocycle,—N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to7-membered)heterocycle; or (b)-phenyl, -(5- or 6-membered)heteroaryl,—N(R_(c))-phenyl, or —N(R_(c))-(5- to 10-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups; each R_(c) is independently —H or —(C₁-C₄)alkyl;each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂; each R₈ and R₉ is independently:(a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, or -phenyl, each of which is unsubstituted orsubstituted with 1 or 2-OH groups; or (b) —H, —CH₂C(halo)₃, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo),—SC(halo)₃, —SCH(halo)₂, —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇,—SR₇, —S(O)R₇, or —S(O)₂R₇; each R₁₁ is independently —CN, —OH,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, or —OC(O)OR₇; each R₁₄ isindependently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,-phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), -(3- to7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy(C₃-C₈)cycloalkyl, —CN, —OH,-halo, —OC(halo)₃, —N₃, —NO₂, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,—O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇,—N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂,—SO₂C(halo)₃, —SO₂(3- to 7-membered)heterocycle, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂; each R₂₀ isindependently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl; each R₂₁ isindependently —H, —(C₁-C₆)alkyl,

each halo is independently —F, —Cl, —Br, or —I; n is the integer 1, 2,or 3; p is the integer 1 or 2; each b is independently 1 or 2; q is theinteger 0, 1, 2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s isthe integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and mis the integer 0, 1, or
 2. 2. The compound of claim 1, wherein X is O.3. The compound of claim 1, wherein R₄ is -halo, optionally —F.
 4. Thecompound of claim 1, wherein R₁ is -halo, optionally —Cl or —F.
 5. Thecompound of claim 1, wherein W is C and the dashed line is absent. 6.The compound of claim 1, wherein W is C and the dashed line is a doublebond.
 7. The compound of claim 1, wherein W is N, R₄ is absent, and thedashed line is absent.
 8. The compound of claim 1, wherein Ar₁ is


9. The compound of claim 1, wherein the Q-group is


10. The compound of claim 8, wherein n is 1, and Q is


11. The compound of claim 10, wherein J is —OR₂₀ or —N(R₂₀)₂, andoptionally is —OR₂₀.
 12. The compound of claim 11, wherein R₂₀ is —H or—(C₁-C₆)alkyl, and optionally is —H.
 13. The compound of claim 10,wherein each Z₃ is independently —H or —(C₁-C₆)alkyl, and optionally is—H.
 14. The compound of claim 10, wherein Z₁ is —H or —CH₂OR₇, andoptionally is —H.
 15. The compound of claim 10, wherein Z₂ is —H,—(C₁-C₆)alkyl, or —CH₂OR₇, and optionally is —H.
 16. The compound ofclaim 1, wherein Ar₂ is


17. The compound of claim 16, wherein each R₁₄ is independently -halo,—C(halo)₃, —(C₁-C₆)alkyl, —OR₇, —OC(halo)₃, or —SO₂C(halo)₃, andoptionally independently is -halo, —C(halo)₃, or —OC(halo)₃.
 18. Thecompound of claim 17, wherein each halo is independently —F or —Cl. 19.The compound of claim 16, wherein s is 1 or
 2. 20. The compound of claim1, wherein Ar₂ is


21. The compound of claim 20, wherein each R₁₄ is independently -halo,—C(halo)₃, —(C₁-C₆)alkyl, —OR₇, —OC(halo)₃, or —SO₂C(halo)₃, andoptionally independently is -halo, —C(halo)₃, or —OC(halo)₃.
 22. Thecompound of claim 21, wherein each halo is independently —F or —Cl. 23.The compound of claim 20, wherein q is 1 or
 2. 24. The compound of claim1, wherein Ar₂ is


25. The compound of claim 24, wherein R₈ and R₉ are independently —H,-halo, or —(C₁-C₆)alkyl, and optionally are independently —H or -halo,wherein each -halo is independently —Cl or —F.
 26. A compound of formulaI.1:

or a pharmaceutically acceptable salt thereof, wherein X is O, S, N—CN,N—OH, or N—OR₁₀; W is N or C; the dashed line denotes the presence orabsence of a bond, and when the dashed line denotes the presence of abond or W is N then R₄ is absent, otherwise R₄ is —H, —OH, —OCF₃, -halo,—(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl, —CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃,—OR₁₀, —SR₁₀, —COOH, —COOR₁₀, —C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀,—NHC(O)R₁₃, —CON(R₁₃)₂, —S(O)₂R₁₀, or —NO₂; R₁₀ is —(C₁-C₄)alkyl; eachR₁₃ is independently: —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl; Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2; Y₁, Y₂, and Y₃ are independently C or N;wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R₂₀group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃; R_(12a) and R_(12b) areindependently —H or —(C₁-C₆)alkyl; E is ═O, ═S, ═C(C₁-C₅)alkyl,═C(C₁-C₅)alkenyl, ═NH(C₁-C₆)alkyl, or ═N—OR₂₀; R₁ is —H, -halo,—(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo); each R₂ isindependently: (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂,—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or (b) agroup of formula Q; wherein Q is

Z₁ is —H, —OR₇, —SR₇, —CH₂—OR₇, —CH₂—SR₇, —CH₂—N(R₂₀)₂, or -halo; Z₂ is—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -phenyl, or -halo;each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl; Z₄ is —H, —OH, —OR₂₀, —(C₁-C₆)alkyl, or—NR₂₀; J is —OR₂₀, —SR₂₀, or —N(R₂₀)₂; provided that at least one R₂group is a group of formula Q, and provided that when Z₁ is —OR₇ or—SR₇, Z₂ in not -halo; each R₃ is independently: (a) —H, —(C₁-C₆)alkyl,or two R₃ groups may form bicyclo group, which gives the followingstructures

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂; each R₈ and R₉ are independently—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —O—CN, —OH, -halo,—N₃, —NO₂, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₁₁ is independently —CN,—OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, or —OC(O)OR₇; each R₁₄ isindependently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,-phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), -(3- to7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —CN, —OH, -halo, OC(halo)₃, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇, —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇,—O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇,—N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂, —SO₂C(halo)₃, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂; each R₂₀ isindependently —H or —(C₁-C₆)alkyl; each halo is independently —F, —Cl,—Br, or —I; n is the integer 1, 2, or 3; p is the integer 1 or 2; each bis independently the integer 1 or 2; q is the integer 0, 1, 2, 3, or 4;r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4,or 5; t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2.27. The compound of claim 26, wherein Q is

Z₁ is —OH, —SH, N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂; Z₂ is —H or—CH₃; each Z₃ is independently —H or —CH₃; and J is —OH, —SH, or—N(R₂₀)₂.
 28. A compound of formula II:

or a pharmaceutically acceptable derivative thereof, wherein X is O, S,N—CN, N—OH, or N—OR₁₀; W is N or C; the dashed line denotes the presenceor absence of a bond, and when the dashed line denotes the presence of abond or W is N then R₄ is absent, otherwise R₄ is —H, —OH, —OCF₃, -halo,—(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl, —CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃,—OR₁₀, —SR₁₀, —COOH, —COOR₁₀, —C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀,—NHC(O)R₁₃, —CON(R₁₃)₂, —S(O)₂R₁₀, or —NO₂; R₁₀ is —(C₁-C₄)alkyl; eachR₁₃ is independently —H, —(C₁-C₄)alkyl, —(C₁-C₄)alkenyl,—(C₁-C₄)alkynyl, or -phenyl; Ar₁ is

Ar₂ is

c is the integer 0, 1, or 2; Y₁, Y₂, and Y₃ are independently C or N;wherein for each Y₁, Y₂, and Y₃ that is N, the N is bonded to one R20group, and for each Y₁, Y₂, and Y₃ that is C, the C is bonded to two R₂₀groups, provided that there are no more than a total of two (C₁-C₆)alkylgroups substituted on all of Y₁, Y₂, and Y₃; R_(12a) and R_(12b) areindependently —H or —(C₁-C₆)alkyl; E is ═O, ═S, ═CH(C₁-C₅)alkyl,═CH(C₁-C₅)alkenyl, —NH(C₁-C₆)alkyl, or ═N—OR₂₀; R₁ is —H, -halo,—(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo); each R₂ isindependently: (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂,—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl, or (b) agroup of formula Q; wherein Q is

Z₁ is —OH, —SH, —N(R₂₀)₂, —CH₂—OH, —CH₂—SH, or —CH₂—N(R₂₀)₂; Z₂ is —H,—CH₃, or —CH₂OR₇ and each Z₃ is independently —H or —CH₃; J is —OH, —SH,or —N(R₂₀)₂; provided that at least one R₂ group is a group of formulaQ; each R₃ is independently: (a) —H or —(C₁-C₆)alkyl; or (b) two R₃groups together form a (C₂-C₆)bridge, which is unsubstituted orsubstituted with 1, 2 or 3 independently selected R₈ groups, and whichbridge optionally contains —HC═CH— within the (C₂-C₆)bridge; or (c) twoR₃ groups together form a —CH₂—N(R_(a))—CH₂— bridge, a

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c); R_(b) is: (a)—H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to 7-membered)heterocycle,—N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to7-membered)heterocycle; or (b)-phenyl, -(5- or 6-membered)heteroaryl,—N(R_(c))-phenyl, or —N(R_(c))-(5- to 10-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups; each R_(c) is independently —H or —(C₁-C₄)alkyl;each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, or —CON(R₂₀)₂; each R₈ and R₉ is independently:(a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, or -phenyl, each of which is unsubstituted orsubstituted with 1 or 2-OH groups; or (b) —H, —CH₂C(halo)₃, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo),—SC(halo)₃, —SCH(halo)₂, —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂,—CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇,—SR₇, —S(O)R₇, or —S(O)₂R₇; each R₁₁ is independently —CN, —OH,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, or —OC(O)OR₇; each R₁₄ isindependently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,-phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), -(3- to7-membered)heterocycle, —(C₁-C₆)haloalkyl, —(C₂-C₆)haloalkenyl,—(C₂-C₆)haloalkynyl, —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,—(C₁-C₆)alkoxy(C₂-C₆)alkyl, —(C₁-C₆)alkoxy(C₂-C₆)alkenyl,—(C₁-C₆)alkoxy(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy(C₃-C₈)cycloalkyl, —CN, —OH,-halo, —OC(halo)₃, —N₃, —NO₂, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,—O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇,—N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)COR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇, —S(O)₂N(R₇)₂,—SO₂C(halo)₃, —SO₂(3- to 7-membered)heterocycle, —CON(R₇)₂,—(C₁-C₅)alkyl-C═NOR₇, —(C₁-C₅)alkyl-C(O)—N(R₇)₂,—(C₁-C₆)alkyl-NHSO₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂; each R₂₀ isindependently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl; each halo isindependently —F, —Cl, —Br, or —I; n is the integer 1, 2, or 3; p is theinteger 1 or 2; each b is independently 1 or 2; q is the integer 0, 1,2, 3, or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0,1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and m is the integer0, 1, or
 2. 29. The compound of claim 28, wherein X is O.
 30. Thecompound of claim 28, wherein R₄ is -halo, optionally —F.
 31. Thecompound of claim 28, wherein R₁ is -halo, optionally —Cl or —F.
 32. Thecompound of claim 28, wherein W is C, and the dashed line is absent. 33.The compound of claim 28, wherein W is C, and the dashed line is adouble bond.
 34. The compound of claim 28, wherein W is N, R₄ is absent,and the dashed line is absent.
 35. The compound of claim 28, wherein Jis —OR₂₀ or —N(R₂₀)₂, and optionally is —OR₂₀.
 36. The compound of claim35, wherein J is —OH.
 37. The compound of claim 28, wherein Z₁ is —H,—OR₇, or —CH₂OR₇, and optionally is —OR₇, wherein R₇ is optionally —H or—(C₁-C₆)alkyl.
 38. The compound of claim 37, wherein Z₁ is —OH.
 39. Thecompound of claim 37, wherein Z₁ is —CH₂OH.
 40. The compound of claim28, wherein Ar₁ is


41. The compound of claim 40, wherein n is
 1. 42. The compound of claim28, wherein Ar₂ is


43. The compound of claim 22, wherein each R₁₄ is independently —H,-halo, —C(halo)₃, —(C₁-C₆)alkyl, —OR₇, —OC(halo)₃, or —SO₂C(halo)₃, andoptionally independently is -halo, —C(halo)₃, or —OC(halo)₃.
 44. Thecompound of claim 43, wherein each -halo is independently —F or —Cl. 45.The compound of claim 44, wherein s is 1 or
 2. 46. The compound of claim28, wherein Ar₂ is


47. The compound of claim 46, wherein each R₁₄ is independently —H,-halo, —C(halo)₃, —(C₁-C₆)alkyl, —OR₇, —OC(halo)₃, or —SO₂C(halo)₃, andoptionally independently is -halo, —C(halo)₃, or —OC(halo)₃.
 48. Thecompound of claim 47, wherein each -halo is independently —F or —Cl. 49.The compound of claim 48, wherein q is 1 or
 2. 50. The compound of claim28, wherein Ar₂ is 2-pyridyl or phenyl, s or q is 1 and the R₁₄substituent is in the 4-position of the Ar₂-substituent.
 51. Thecompound claim 28, wherein Ar₂ is 2-pyridyl or phenyl, s or q is 2 andthe R₁₄ substituents are in the 3- and 4-positions of theAr₂-substituent.
 52. The compound of claim 28, wherein Ar₂ is


53. The compound of claim 52, wherein R₈ and R₉ are independently —H,-halo, or —(C₁-C₆)alkyl, and optionally are independently —H or -halo,wherein each -halo is independently —Cl or —F.
 54. The compound of claim28, wherein R₁ is —Cl, Z₂ is —H, and Z₃ is —H.
 55. The compound of claim54, wherein R₄ is —F.
 56. The compound of claim 28, wherein W is C, X isO, Z₁ is —OH and J is —OH.
 57. The compound of claim 28, wherein W is C,X is O, Z₁ is —CH₂OH and J is —OH.
 58. The compound of claim 28, whereinW is C, the dashed line is a double bond, X is O, Z₁ is —OH, J is —OH,R₁ is -halo, and Ar₁ is


59. The compound of claim 28, wherein W is C, the dashed line is adouble bond, X is O, Z₁ is —CH₂OH, J is —OH, R₁ is -halo, and Ar₁ is


60. The compound of claim 28, wherein W is C, X is O, Z₁ is —OH, J is—OH, R₁ is -halo, R₄ is -halo, and Ar₁ is


61. The compound of claim 28, wherein W is C, X is O, Z₁ is —CH₂OH, J is—OH, R₁ is -halo, R₄ is -halo, and Ar₁ is


62. The compound of claim 28, wherein W is C, the dashed line is adouble bond, X is O, Z₁ is —OH, J is —OH, R₁ is -halo, Ar₁ is

and Ar₂ is


63. The compound of claim 62, wherein R₁ is —Cl, Z₂ is —H, and Z₃ is —H.64. The compound of claim 28, wherein W is C, the dashed line is adouble bond, X is O, Z₁ is —CH₂OH, J is —OH, R₁ is -halo, Ar₁ is

and Ar₂ is


65. The compound of claim 64, wherein R₁ is —Cl, Z₂ is —H, and Z₃ is —H.66. The compound of claim 28, wherein W is C, X is O, Z₁ is —OH, J is—OH, R₁ is -halo, R₄ is -halo, Ar₁ is

and Ar₂ is


67. The compound of claim 66, wherein R₁ is —Cl, R₄ is —F, Z₂ is —H, andZ₃ is —H.
 68. The compound of claim 28, wherein W is C, X is O, Z₁ is—CH₂OH, J is —OH, R₁ is -halo, R₄ is -halo, Ar₁ is

and Ar₂ is


69. The compound of claim 68, wherein R₁ is —Cl, R₄ is —F, Z₂ is —H, andZ₃ is —H.
 70. The compound of claim 28, wherein W is C, the dashed lineis a double bond, X is O, Z₁ is —OH, J is —OH, R₁ is -halo, Ar₁ is

and Ar₂ is


71. The compound of claim 70, wherein R₁ is —Cl, Z₂ is —H, and Z₃ is —H.72. The compound of claim 28, wherein W is C, the dashed line is adouble bond, X is O, Z₁ is —CH₂OH, J is —OH, R₁ is -halo, Ar₁ is

and Ar₂ is


73. The compound of claim 72, wherein R₁ is —Cl, Z₂ is —H, and Z₃ is —H.74. The compound of claim 28, wherein W is C, X is O, Z₁ is —OH, J is—OH, R₁ is -halo, R₄ is -halo, Ar₁ is

and Ar₂ is


75. The compound of claim 74, wherein R₁ is —Cl, R₄ is —F, Z₂ is —H, andZ₃ is —H.
 76. The compound of claim 28, wherein W is C, X is O, Z₁ is—CH₂OH, J is —OH, R₁ is -halo, R₄ is -halo, Ar₁ is

and Ar₂ is


77. The compound of claim 76, wherein R₁ is —Cl, R₄ is —F, Z₂ is —H, andZ₃ is —H.
 78. A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein X is O, S, N—CN,N—OH, or N—OR₁₀; W is N or C; the dashed line denotes the presence orabsence of a bond, and when the dashed line denotes the presence of abond or W is N then R₄ is absent, otherwise R₄ is —H, —OH, —OCF₃, -halo,—(C₁-C₆)alkyl, —CH₂OH, —CH₂Cl, —CH₂Br, —CH₂I, —CH₂F, —CH(halo)₂, —CF₃,—OR₁₀, —SR₁₀, —COOH, —COOR₁₀, —C(O)R₁₀, —C(O)H, —OC(O)R₁₀, —OC(O)NHR₁₀,—NHC(O)R₁₃, —CON(R₁₃)₂, —S(O)₂R₁₀, or —NO₂; each R₃ is independently:(a) —H or —(C₁-C₆)alkyl; or (b) two R₃ groups together form a(C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups, and which bridge optionally contains—HC═CH— within the (C₂-C₆)bridge; or (c) two R₃ groups together form a—CH₂—N(R₃)—CH₂— bridge, a

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(O)—R_(c),—(CH₂)—C(O)—OR_(c), —(CH₂)—C(O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(O)₂—R_(c); R_(b) is: (a)—H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to 7-membered)heterocycle,—N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl, or —N(R_(c))-(3- to7-membered)heterocycle; or (b)-phenyl, -(5- or 6-membered)heteroaryl,—N(R_(c))-phenyl, or —N(R_(c))-(5- to 10-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₇ groups; each R_(c) is independently —H or —(C₁-C₄)alkyl; mis the integer 0, 1, or 2; wherein Ar₁ is:

R₁ is —Cl, —F, —CF₃, or —CH₃; wherein Ar₂ is:

R₁₄ is —H, —Cl, —F, —Br, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is —H,—CF₃, —OCF₃, —Cl, or —F; R_(14′) is —H, —Cl, —F, —Br, —CF₃, —OCF₃,—(C₁-C₆)alkyl, —SO₂CF₃, —SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or—OCH(CH₃)₂, and optionally is —H, —CF₃, —OCF₃, —Cl, or —F; and R₈ and R₉are independently —H, —Cl, —Br, —F, —CH₃, —OCH₃, —OCH₂CH₃, —CF₃, —OCF₃,iso-propyl, or tert-butyl.
 79. The compound of claim 78, wherein X is O.80. The compounds of claim 78, wherein R₄ is -halo, and optionally —F.81. The compound of claim 78, wherein R₁ is —Cl, —F, or —CF₃.
 82. Thecompound of claim 78, wherein W is C and the dashed line is absent. 83.The compound of claim 78, wherein W is C and the dashed line is a doublebond.
 84. The compound of claim 78, wherein W is N, R₄ is absent, andthe dashed line is absent.
 85. The compound of claim 78, wherein thechiral carbon atom of the Q-group has the (S)-configuration:


86. The compound of claim 78, wherein the chiral carbon atom of theQ-group has the (R)-configuration:


87. The compound of claim 78, wherein m is
 0. 88. The compound of claim78, wherein m is 1 and R₃ is —(C₁-C₆)alkyl, optionally R₃ is —CH₃ or—CH₂CH₃.
 89. The compound of claim 78, wherein Ar₂ is


90. The compound of claim 78, wherein Ar₂ is


91. The compound of claim 78, wherein Ar₂ is

wherein R₁₄ is —H, —Cl, —F, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is—CF₃, —OCF₃, —Cl, or —F.
 92. The compound of claim 78, wherein Ar₂ is

wherein R_(14′) is —H, —Cl, —F, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is—CH₃, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —Cl, or —F.
 93. The compound ofclaim 78, wherein Ar₂ is

wherein R_(14′) is —H, —Cl, —F, —CF₃, —OCF₃, —(C₁-C₆)alkyl, —SO₂CF₃,—SO₂(C₁-C₆)alkyl, —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂, and optionally is—CH₃, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —Cl, or —F.
 94. The compound ofclaim 78, wherein Ar₂ is


95. The compound of claim 78, wherein Ar₂ is

wherein R₈ and R₉ are independently —H, —Cl, —F, —CH₃, —OCH₃, —OCH₂CH₃,—CF₃, —OCF₃, iso-propyl, or tert-butyl.
 96. The compound of claim 1,wherein the pharmaceutically acceptable derivative is a pharmaceuticallyacceptable salt.
 97. The compound of claim 28, wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt.
 98. The compound of claim 78, wherein the pharmaceuticallyacceptable derivative is a pharmaceutically acceptable salt.
 99. Acomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable derivative thereof and a pharmaceutically acceptable carrieror excipient.
 100. A composition comprising the compound of claim 28 ora pharmaceutically acceptable derivative thereof and a pharmaceuticallyacceptable carrier or excipient.
 101. A composition comprising thecompound of claim 78 or a pharmaceutically acceptable derivative thereofand a pharmaceutically acceptable carrier or excipient.
 102. A methodfor treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal,comprising administering to an animal in need thereof, an effectiveamount of the compound of claim 1 or a pharmaceutically acceptablederivative thereof.
 103. A method for treating or preventing pain, UI,an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the compound of claim 28or a pharmaceutically acceptable derivative thereof.
 104. A method fortreating or preventing pain, UI, an ulcer, IBD, or IBS in an animal,comprising administering to an animal in need thereof, an effectiveamount of the compound of claim 78 or a pharmaceutically acceptablederivative thereof.
 105. A method of inhibiting TRPV1 function in a cellcomprising contacting a cell capable of expressing TRPV1 with aneffective amount of the compound of claim 1 or a pharmaceuticallyacceptable derivative thereof.
 106. A method of inhibiting TRPV1function in a cell comprising contacting a cell capable of expressingTRPV1 with an effective amount of the compound of claim 28 or apharmaceutically acceptable derivative thereof.
 107. A method ofinhibiting TRPV1 function in a cell comprising contacting a cell capableof expressing TRPV1 with an effective amount of the compound of claim 78or a pharmaceutically acceptable derivative thereof.